CLINICAL REPORT
Ocular Pterygium—Digital Keloid Dysplasia Hugo Abarca,1y Anne E Christensen Mellgren,2,3y Milana Trubnykova,1 Olav H. Haugen,2,3 Gunnar Høvding,2,3 Ka˚re Steinar Tveit,4 Gunnar Houge,3,5 Cecilie Bredrup,2,5 and Raoul C Hennekam6* 1
Instituto Nacional de Salud del Nino, Lima, Peru Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway
2 3
Department of Clinical Medicine, University of Bergen, Bergen, Norway
4
Department of Dermatology, Haukeland University Hospital, Bergen, Norway Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
5 6
Department of Pediatrics, Emma Children’s Hospital and Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands Manuscript Received: 3 March 2014; Manuscript Accepted: 3 July 2014
We describe an adolescent Peruvian male with marked, aggressive ingrowth of conjunctiva (pterygium-like) over the cornea associated with keloid formation on his distal limbs. He has in addition camptodactyly of all fingers and to some extent of his toes, and unusual skin pigmentations. He resembles an earlier described family from Norway in which a mother and two children showed a similar combination of signs. We present the follow-up of the Norwegian family. The entity resembles the Penttinen syndrome but can be differentiated due to the early aging in the latter, which is lacking in the presently reported entity. We suggest naming this entity ocular pterygium–digital keloid dysplasia. The condition follows likely an autosomal dominant pattern of inheritance. Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Abarca H, Mellgren AEC, Trubnykova M, Haugen OH, Høvding G, Tveit KS, Houge G, Bredrup C, Hennekam RC. 2014. Ocular pterygium—digital keloid dysplasia. Am J Med Genet Part A 164A:2901–2907.
and Bertelsen. We suggest naming this entity ocular pterygiumdigital keloid dysplasia.
CLINICAL REPORT Key words: keloid; childhood ocular pterygium; camptodactyly; autosomal dominant
INTRODUCTION Keloid formation can be defined as increased scar tissue formation not being in accordance to the trauma. Keloids may impair function by restriction of the skin and decrease of joint mobility, can be aesthetically disfiguring, and may cause intense symptomatic distress due to the itching and pain, which often accompanies keloids. Keloids do not occur frequently in syndromes and if they occur together with other manifestations, they are located at upper thorax, shoulders and upper arms, which are also the predilection sites of isolated keloids. In 1998 Haugen and Bertelsen [1998] reported on a mother and two sons with ingrowth of conjunctival tissue that gradually covered the whole cornea and progressive keloid formation in their hands and fingers. A single family with possibly the same entity has been reported since [Balaji et al., 1991; Booth and Hodgkins, 2006]. Here we report on a patient from a second family with very similar findings, and provide an update on the family reported by Haugen
Ó 2014 Wiley Periodicals, Inc.
The proband was the fifth child of nonconsanguineous Peruvian parents. There are several persons in the family with ocular pterygia: the parents of the proband are both construction workers. Father developed pterygia from the age of 30 years and mother had minor pterygia from the age of about 20 years. Neither has undergone surgery. Mother has one brother who underwent successful surgery for his pterygia. There are no other known eye diseases in the family, and no one is known to have keloid formation. The proband is the fifth child of these parents. Their first children were twins born at 8 months weighing 2700 g. Both died in infancy, Conflict of interest: None y Hugo Abarca and Anne E Christensen Mellgren have contributed equally to the manuscript. Grant sponsor: Western Norway Regional Health Authority; Grant numbers: 911466, 911688. Correspondence to: Dr Raoul C Hennekam, Department of Pediatrics, Room 7-236, AMC, Meibergdreef 9, 1105AZ Amsterdam. E-mail [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 14 August 2014 DOI 10.1002/ajmg.a.36713
2901
2902 one due to an infection, and the other of unknown reasons. Their next son died in infancy because of an infection as well. Mother subsequently gave birth to a healthy daughter who never developed problems similar to the proband. All children were born by caesarean section. Because of this obstetric history the pregnancy of the proband was ended by caesarean at 34 weeks. Birth weight was 2500 g and length was stated to have been normal. He received “light therapy” at home for 4 weeks because of prolonged hyperbilirubinaemia. His psychomotor development was normal; he could sit at 6 months, and walk at 16 months. His initial speech development was somewhat slow (first words at 2 years) but subsequently his cognitive development was completely normal. Since childhood he complained of early fatigability, which persisted into adulthood. Cardiac examination showed normal cardiac anatomy and function. He was found to have ingrown toenails which were surgically corrected, after which keloid formation started at his toes. Non-operated toes developed keloids as well, which was possibly related to nail bed irritation, and he had also a skin lesion on his right sole. The keloids increased with time, and after a biopsy was taken rapid growth was noted. He had congenital mildly decreased mobility of his fingers, showing in only faint distal flexion creases of all fingers, but initially no keloid formation at his hands. Radiological studies failed to show bony abnormalities of the hands. At 5 years reduced vision was first noticed. At 7 years, an aggressive pterygium was diagnosed on the right eye, starting from the nasal side and spreading over the cornea. A year later a similar pterygium was noticed on the left eye. At 9 years, he underwent pterygium excision in both eyes, in the left eye Mitomycin C was applied, but the pterygia recurred. Repeated surgery on the right eye was performed but without success. Subsequently, he developed a right-sided symblepharon. At 18 years a keratoprosthesis was implanted in the right eye, with initial success and regain of some visual acuity, but subsequent loss of vision due to dislocation of the keratoprosthesis to the interior of the eye. He has subsequently developed phthisis in the right eye, and has visual acuity of light perception only. In the left eye visual acuity was 0.2 (Snellen) despite recurrence of the pterygium. The temporal part of the cornea of the left eye is still clear (Fig. 3). The proband developed around 15 years of age darkly pigmented skin lesions on trunk and limbs, which sometimes were confluent but sometimes also disappeared. Clinically the skin changes resembled brown angiokeratomas. At that time hammertoes developed, especially of the right 2nd, 3rd, and 4th toe. The camptodactyly had gradually increased and he developed two small keloids, both after trauma, on a middle finger. At age 19 years he was diagnosed with photosensitive dermatitis in his face needing treatment (methotrexate). On examination at age 19 years the proband was a normally intelligent adolescent, height 167 cm (10th centile) and weight 60 kg (30th centile), and head circumference 57.0 cm (50th centile). He had normal hair, an irregularly formed right eyebrow and blepharophimosis, interpreted to be secondary to the earlier surgery (Fig. 1). There were tongues of conjunctival tissue invading the cornea in both eyes, in the right eye covering the whole cornea (Fig. 2), narrow nasal bridge, prominent nose, normal teeth, somewhat high palate, and pits of the posterior helices. He had a normal trunk with mildly increased fat deposits, a thoracic kypho-
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. Face of the proband. Note the narrow nasal bridge and prominent nose.
sis, and normal male genitalia. There was mild hyperhidrosis of face and trunk. Mobility in shoulders and elbows was normal, and hands showed camptodactyly of all fingers. There were small keloids on the middle finger (Fig. 3a). There were only faint flexion creases visible over the distal interphalangeal joints. Mobility in hips and knees was normal. He had hammertoes, more marked on the right side, shortened distal phalanges of the halluces, and bluish discolored keloid tissue on the dorsum of both halluces with some spreading to the dorsum of the feet (Fig. 3b).
UPDATE OF HAUGEN AND BERTELSEN REPORT The family consists of an affected mother (proband) and two affected sons. The parents of the proband had reportedly normal eyes and no keloids. At 2 years ingrowth of scar tissue was observed in both eyes of the proband. Despite surgery the ingrowth progressed and became confluent when she was 8 years of age. From 20 years on she developed keloid-like scars on the flexor side of the fingers causing flexion contractures (Fig. 4a). In her sixties she quite abruptly developed large granuloma-annulare-like eczemas on the posterior aspect of both upper arms. In one of these lesions a sarcoma developed that was successfully treated. The number of cutaneous fibromas increased over the years, especially on the central face, trunk, and extremities. At 73 years she developed an adenocarcinoma of the endometrium, and she died at age 75 years. The oldest son of the proband presented with progressive, superficial grayish corneal opacities in the left eye at 1 year of age and in the right eye at 2 years. At 3 years multiple tongue-like ingrowths approached the center of the corneas (Fig. 4b). Surgical interventions in the right eye were unsuccessful. In his second decade he developed multiple broad-based fibromas on his trunk and neck. At 21 years he developed keloids on his fingers but these were less pronounced compared to those in his mother and brother. At 35 years keloids developed on his halluces (Fig. 4a). The youngest son of the proband had normal eyes until the age of six when thin, grey-white tissue became apparent at the upper temporal limbal region of the right eye. The changes progressed slowly and at 18 years of age covered the whole cornea. The left eye
ABARCA ET AL.
2903
FIG. 2. Eyes of the proband at 19 year of age. Note phthisic right eye (axial length 16mm), extensive scarring due to conjunctival ingrowth over the cornea and previous surgery. The symblepharon of the lower eyelid is secondary to surgery. The left eye (23 mm) shows conjunctival ingrowth nasally and superiorly; the temporal part is relatively spared.
FIG. 3. a. Right hand of the proband and detail of left middle finger. Note the camptodactyly and only faint distal interphalangeal flexion creases. The left middle finger has two small keloids both as results of minor trauma. Fig. 3b. Feet of the proband. Note extensive keloid formation. The keloids on both halluces appeared after surgery for ingrown nails. The keloids on the other toes apparently developed spontaneously.
2904
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 4. a. Distal limbs of family reported by Haugen and Bertelsen [1998]. Left panel: Large keloids on the fingers of the proband (mother) causing syndactyly and restricted movements of especially the index and middle finger, and extending from the back of the fingers to the distal back of the hands. Middle panel: Keloids on the plantar side of the halluces of the eldest son. Right panel: Keloids on the right hand of the youngest son, ending just proximal to the nail bed. Fig. 4b. Eyes of family members reported by Haugen and Bertelsen [1998]. Left panel: The un-operated left eye of the eldest son, showing vascularized tissue covering the cornea completely. Right panel: The left eye of the youngest son showing conjunctival ingrowth on the cornea resembling pterygium.
was unaffected until the age of 20, when similar changes appeared, and in less than four years the optic axis was covered (Fig. 4b). At 15 years slowly progressive and bilaterally symmetric keloids developed on the third, fourth, and fifth fingers covering the dorsal and lateral aspect of the distal phalanges (Fig. 4a). At 28 years keloids arose on the plantar side of both halluces. In addition he developed erythema in the face, and multiple fibromas in his face, neck, shoulders, and back.
DISCUSSION We report on a single individual who has aggressive, early ocular pterygium-like formation with an unusual progression and lack of response to treatment. In addition he has early onset keloid formation on all distal limbs. These manifestations resemble the manifestations described in the three members of a Norwegian family to a great extent (Table I). The present proband showed camptodactyly of hands and feet from early on. Marked camptodactyly of hands were seen in the proband of the Norwegian family, but this was secondary to the extensive keloid formation on the ventral side of her fingers. The present proband has an increased thoracic kyphosis and truncal fat deposits, which were not evident in the Norwegian family. As the major findings in the proband are very similar to the findings in the family described by Haugen and Bertelsen, it seems likely they have the same entity. We suggest
naming the entity ocular pterygium – digital keloid dysplasia, as there are ocular pterygia, keloids on the digits, and the early onset, the continuous progression during life and histological findings fit a dysplasia. Booth and Hodgkins [2006] provided an update of a family reported earlier on by Balaji and colleagues [1991]. In the first report the family was reported to have Ebstein anomaly (displacement of the septal and posterior tricuspid valve leaflets) and restricted finger and toe movements [Balaji et al., 1991]. The update described that one member had ingrowth of fibrous tissue in the cornea on one side and multiple keloids on trunk and limbs [Booth and Hodgkins, 2006]. It was stated that by history several other family members had multiple keloids as well. It remains uncertain whether this family has ocular pterygium-digital dysplasia, due to the presence of eye manifestations in only one of multiple affected members, presence of keloids also on the trunk, and presence of Ebstein anomaly. A pterygium is a common fibrovascular dysplasia affecting the bulbar conjunctiva, more frequently located on the nasal than temporal limbus. In addition to discomfort it can give rise to visual problems if it crosses the pupillary axis. In peri-equatorial countries and in high altitude regions a high incidence of pterygia is seen. Pterygia are assumed to be caused by high exposure to ultraviolet light. Additional risk factors include family history, increasing age, and male gender. Certain groups, such as outdoor workers, have an
ABARCA ET AL.
2905
TABLE I. Main Characteristics in the Present Proband Compared to The Updated Findings Reported by Haugen and Bertelsen [1998] and to Penttinen Syndrome. Penttinen syndromea
Haugen and Bertelsen, 1998 Cognition Growth (centile) Ocular pterygia Age diagnosis Progression Age 1st surgery Keloid (age) Hands Feet Other Thin, translucent skin Abnormal skin pigmentation Abnormal hair pigmentation Acro-osteolysis Short, broad digits Camptodactyly Fingers Toes Face Hair Nasal bridge (Pre)maxilla Nose Thin upper Vermilion Hyperkyphosis Lipodystrophy Other a
Proband Nl 167 cm (P10) bilat 7yr þþ 9yr 4yr þ þþ þ
P1 (Mother) Nl 175 cm (P90) bilat 2yr þþ 4yr 20yr þþ right arm
P2 (son) Nl 170 cm (P15) bilat 1yr þþ 3yr 22yr þ þ þ
P3 (son) Nl 173 cm (P25) bilat 6yr þþ 23yr 15yr þ þ þ
þ þ
þþ
nl narrow nl prominent þ (trunkal fat deposits)
nl multiple fibromas
P1 Nl P50–75
P2 Nl >3SD
P3 Nl 3SD
bilat 9yr ? ?
2yr þ þ elbows, knees þ þ þ þ
bilat 9yr ? ? (3yr) þ þ buttocks þ ? þ þ
þþ
þþ
þþ
nl
nl
sparse broad retracted þ þ
sparse retracted þ þ þ
sparse retracted þ þ þ
multiple fibromas
multiple fibromas
bifid uvula corneal clouding
wide fontanel
craniosynostosis Epilepsy VSD
þ ? þ þ
P1: Penttinen et al., 1997; P2 and P3: Zufferey et al., 2012.
increased incidence to develop pterygia [Liu et al., 2013]. The prevalence of pterygium in Peru has been described as high as 31%. However, in less than 1% of the cases the pterygium extended more than halfway to the center of the cornea and no patients below 20 years of age were described [Rojas and Ma´laga, 1986]. Since the family of the proband has several risk factors for developing pterygium (they live at a high altitude and are outdoor workers), pterygium development is not unexpected in early adulthood, which is the case in the affected family members except the proband. In addition, the natural history in the other family members is as expected for normal pterygium development and different from the course in the proband. Therefore it is unlikely that pterygium development in family members is causally related to the aggressive conjunctival ingrowth seen in the proband. Pterygium formation in children is rare and can in most cases be managed conservatively [Monga et al., 2012]. One family in which aggressive pterygium was
present in three second degree family members, of which two developed ocular changes in childhood (at 6 and 4 years, respectively) has been described. No extraocular signs or symptoms were reported, in particular not with respect to the skin [Islam and Wagoner, 2001]. Another main finding in the present patient is the keloid formation at the distal limbs. There are only a limited number of Mendelian entities that go along with keloid formation. Some of the connective tissue disorders such as Ehlers-Danlos syndrome type IV [Burk et al., 2007] and lateral meningocele syndrome [Chen et al., 2005] can show keloid formation. Goeminne syndrome is characterized by a progressive torticollis, kyphosis, pectus formation, umbilical herniae, varicose veins, normal intelligence, and keloids on trunk and limbs, including hands [Fryns and Gevers, 2003], and this condition may in fact also be a connective tissue disorder. One of us (RCH) has seen several males and females
2906 with a phenotype that resembles frontometaphyseal dysplasia but without detectable Filamin A mutations, who had numerous rounded keloids widely spread over their body. The most frequently occurring syndrome that goes along with keloid formation in a significant percentage of patients is Rubinstein-Taybi syndrome [Hennekam, 2006]. A recent study showed that 24% of all Rubinstein-Taybi patients develop keloids [Van de Kar et al., in press]. Keloids in this entity are located on upper thorax, shoulders and upper arms, and rarely elsewhere. Myhre syndrome is characterized by intellectual disability, short stature with a stocky body build, hearing loss, an unusual face, and keloids can occur in the upper airways (nose; larynx) [McGowan et al., 2011]. In oculo-ectodermal syndrome macrocephaly, areas of aplasia cutis of the scalp, epibulbar dermoids, and areas of hyperpigmentation of the skin can go along with keloid formation as well [Evers et al., 1994]. Several families have been described with a phenotype that resembles Bardet-Biedl syndrome without the distal limb anomalies but with deafness, cataract, and keloid formation as additional manifestations [Boor et al., 1993]. Heyen and co-workers reported on several individuals from a single family who had a large optic cupto-disc ratio, camptodactyly and keloid formation on trunk or proximal limbs [Heyen et al., 2008]. Finally, keloid formation has rarely been described in chromosome imbalances such as Turner syndrome and deletions of the terminal part of chromosome 19p [Archer et al., 2005], and in a small number of case reports [Leung et al., 1988; Coffin, 1990; Anandan et al., 2008]. In none of the above entities progressive conjunctival ingrowth on the cornea was seen, and only very infrequently keloids develop on their hands and feet. There is a single entity in which ocular pterygia have been reported together with keloids on the distal limbs, i.e. Penttinen syndrome [Penttinen et al., 1997; Zufferey et al., 2012]. The three patients reported with this entity may have ocular pterygia that arise at a very young age as in ocular pterygium-digital keloid dysplasia, and may also have keloid formation on the back of the hands and feet (Table I). However, in Penttinen syndrome the affected individuals may show somatic overgrowth, facial characteristics (sparse hair, retracted maxilla and pre-maxilla, and thin upper vermillion), an unusual thin and translucent skin, progressive acro-osteolysis, progressive lipodystrophy, and short and broad digits, especially thumbs and halluces. We concur with Zufferey and co-workers [2013] that despite the resemblances the differences are sufficient to discern the two entities. We conclude that the present patient resembles the family reported by Haugen and Bertelsen [1998] but not any other entity, The occurrence of the syndrome in two generations, both sexes, and absence of consanguinity all point to an autosomal dominant pattern of inheritance. The cause is unknown. We have initiated a molecular study using next generation sequencing techniques in order to detect the gene causing this entity.
ACKNOWLEDGMENTS We thank the family for their participation in this study. We thank Eyvind Rødahl for useful discussions and Marte Emilie Sandvik Haaland and Lisbet Sviland for professional assistance. This study was supported by grants from the Western Norway Regional Health
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Authority (911466 and 911688 to C.B). None of the authors have any conflicts of interests.
REFERENCES Anandan V, Parveen B, Prabhavathy D, Priyavarthini V. 2008. Adams Oliver syndrome—A variant. Int J Dermatol 47:1260–1262. Archer HL, Gupta S, Enoch S, Thompson P, Rowbottom A, Chua I, Warren S, Johnson D, Ledbetter DH, Lese-Martin C, Williams P, Pilz DT. 2005. Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13.3-pter. Am J Med Genet 136A:38–44. Balaji S, Dennis NR, Keeton BR. 1991. Familial Ebstein anomaly: A report of six cases in two generations associated with mild skeletal abnormalities. Br Heart J 66:26–28. Boor R, Herwig J, Schrezenmeir J, Pontz BF, Schonberger W. 1993. Familial insulin resistant diabetes associated with acanthosis nigricans, polycystic ovaries, hypogonadism, pigmentary retinopathy, labyrinthine deafness, and mental retardation. Am J Med Genet 45:649–653. Booth AJ, Hodgkins PR. 2006. Pseudopterygium arising in a patient with multiple keloids. J Pediatr Ophthalmol Strabis 43:49–51. Burk CJ, Aber C, Connelly EA. 2007. Ehlers-Danlos syndrome type IV: Keloidal plaques of the lower extremities, amniotic bands, limb deformities, and a new mutation. J Am Acad Dermatol 56 (Suppl 2): S53–S54. Chen KM, Bird L, Barnes P, Barth R, Hudgins L. 2005. Lateral meningocele syndrome: Vertical transmission and expansion of the phenotype. Am J Med Genet 133A:115–121. Coffin GS. 1990. Developmental retardation with unusual facies, arthritis, and hearing impairment. Dysmorph Clin Genet 4:103–109. Coroneo MT, Chui JJY. 2013. Pterygium In: Holland EJ, Mannis MJ, Barry Lee W, Ocular surface disease:Cornea, conjuntiva and tear film. Philadelphia: Elsevier Sauders. p. 125–144. Evers MEJW, Dijkman-Neerincx RHM, Hamel BCJ. 1994. Oculo-ectodermal syndrome: A new case. Am J Med Genet 53:378–379. Fryns JP, Gevers D. 2003. Goeminne syndrome (OMIM 314300): Another male patient 30 years later. Genet Counsel 14:109–111. Haugen OH, Bertelsen T. 1998. A new hereditary conjunctivo-corneal dystrophy associated with dermal keloid formation. Acta Ophthalmol Scand 76:461–465. Hennekam RCM. 2006. Rubinstein-Taybi syndrome. Eur J Hum Genet 14:981–985. Heyen CA, Delk PR, Bull MJ, Weaver DD. 2008. A report of an apparent new genetic syndrome consisting of joint contractures, keloids, large optic cup-to-disc ratio and renal stones. Am J Med Genet 146A:3120– 3125. Islam SI, Wagoner MD. 2001. Pterygium in young members of one family. Cornea 20:708–710. Leung RSC, Beer WE, Mehta HK. 1988. Aplasia cutis congenita presenting as a familial triad of atrophic alopecia, ocular defects and a peculiar scarring tendency of the skin. Br J Dermatol 118:715–720. Liu L, Wu J, Geng J, Yuan Z, Huang D. 2013. Geographical prevalence and risk factors for pterygium: A systematic review and meta-analysis. BMJ Open 3:e003787. McGowan R, Gulati R, McHenry P, Cooke A, Butler S, Keng WT, Murday V, Whiteford M, Dikkers FG, Sikkema-Raddatz B, van Essen T, Tolmie J. 2011. Clinical features and respiratory complications in myhre syndrome. Eur J Med Genet 54:553–559.
ABARCA ET AL.
2907
Monga S, Gupta A, Kekunnava R, Goyal S, Vemuganti GK, Sachdeva V. 2012. Childhood pterygium; a descriptive study of 19 cases presented to a tertiary eye care center. Am J Ophthalmol 154:859–864.
Van de Kar A, Houge G, Shaw AC, Van Belzen MJ, Peters DJM, Hennekam RC. Keloids in Rubinstein-Taybi syndrome: A clinical study. Br J Dermatol. In press.
Penttinen M, Niemi KM, Vinkka-Puhakka H, Johansson R, Aula P. 1997. New progeroid disorder. Am J Med Genet 69:182–187.
Zufferey F, Hadj-Rabia S, De Sandre-Giovannoli A, Dufier JL, Leheup B, Schweitze C, Bodemer C, Cormier-Daire V, Le Merrer M. 2012. Acroocteolysis, keloid like-lesions, distinctive facial features, and overgrowth: Two newly recognized patients with premature aging syndrome, penttinen type. Am J Med Genet 161A:1786–1791.
Rojas JR, Ma´laga H. 1986. Pterygium in Lima, Peru. Ann Ophthalmol 18:147–149.
Ocular Pterygium—Digital Keloid Dysplasia Hugo Abarca,1y Anne E Christensen Mellgren,2,3y Milana Trubnykova,1 Olav H. Haugen,2,3 Gunnar Høvding,2,3 Ka˚re Steinar Tveit,4 Gunnar Houge,3,5 Cecilie Bredrup,2,5 and Raoul C Hennekam6* 1
Instituto Nacional de Salud del Nino, Lima, Peru Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway
2 3
Department of Clinical Medicine, University of Bergen, Bergen, Norway
4
Department of Dermatology, Haukeland University Hospital, Bergen, Norway Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
5 6
Department of Pediatrics, Emma Children’s Hospital and Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands Manuscript Received: 3 March 2014; Manuscript Accepted: 3 July 2014
We describe an adolescent Peruvian male with marked, aggressive ingrowth of conjunctiva (pterygium-like) over the cornea associated with keloid formation on his distal limbs. He has in addition camptodactyly of all fingers and to some extent of his toes, and unusual skin pigmentations. He resembles an earlier described family from Norway in which a mother and two children showed a similar combination of signs. We present the follow-up of the Norwegian family. The entity resembles the Penttinen syndrome but can be differentiated due to the early aging in the latter, which is lacking in the presently reported entity. We suggest naming this entity ocular pterygium–digital keloid dysplasia. The condition follows likely an autosomal dominant pattern of inheritance. Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Abarca H, Mellgren AEC, Trubnykova M, Haugen OH, Høvding G, Tveit KS, Houge G, Bredrup C, Hennekam RC. 2014. Ocular pterygium—digital keloid dysplasia. Am J Med Genet Part A 164A:2901–2907.
and Bertelsen. We suggest naming this entity ocular pterygiumdigital keloid dysplasia.
CLINICAL REPORT Key words: keloid; childhood ocular pterygium; camptodactyly; autosomal dominant
INTRODUCTION Keloid formation can be defined as increased scar tissue formation not being in accordance to the trauma. Keloids may impair function by restriction of the skin and decrease of joint mobility, can be aesthetically disfiguring, and may cause intense symptomatic distress due to the itching and pain, which often accompanies keloids. Keloids do not occur frequently in syndromes and if they occur together with other manifestations, they are located at upper thorax, shoulders and upper arms, which are also the predilection sites of isolated keloids. In 1998 Haugen and Bertelsen [1998] reported on a mother and two sons with ingrowth of conjunctival tissue that gradually covered the whole cornea and progressive keloid formation in their hands and fingers. A single family with possibly the same entity has been reported since [Balaji et al., 1991; Booth and Hodgkins, 2006]. Here we report on a patient from a second family with very similar findings, and provide an update on the family reported by Haugen
Ó 2014 Wiley Periodicals, Inc.
The proband was the fifth child of nonconsanguineous Peruvian parents. There are several persons in the family with ocular pterygia: the parents of the proband are both construction workers. Father developed pterygia from the age of 30 years and mother had minor pterygia from the age of about 20 years. Neither has undergone surgery. Mother has one brother who underwent successful surgery for his pterygia. There are no other known eye diseases in the family, and no one is known to have keloid formation. The proband is the fifth child of these parents. Their first children were twins born at 8 months weighing 2700 g. Both died in infancy, Conflict of interest: None y Hugo Abarca and Anne E Christensen Mellgren have contributed equally to the manuscript. Grant sponsor: Western Norway Regional Health Authority; Grant numbers: 911466, 911688. Correspondence to: Dr Raoul C Hennekam, Department of Pediatrics, Room 7-236, AMC, Meibergdreef 9, 1105AZ Amsterdam. E-mail [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 14 August 2014 DOI 10.1002/ajmg.a.36713
2901
2902 one due to an infection, and the other of unknown reasons. Their next son died in infancy because of an infection as well. Mother subsequently gave birth to a healthy daughter who never developed problems similar to the proband. All children were born by caesarean section. Because of this obstetric history the pregnancy of the proband was ended by caesarean at 34 weeks. Birth weight was 2500 g and length was stated to have been normal. He received “light therapy” at home for 4 weeks because of prolonged hyperbilirubinaemia. His psychomotor development was normal; he could sit at 6 months, and walk at 16 months. His initial speech development was somewhat slow (first words at 2 years) but subsequently his cognitive development was completely normal. Since childhood he complained of early fatigability, which persisted into adulthood. Cardiac examination showed normal cardiac anatomy and function. He was found to have ingrown toenails which were surgically corrected, after which keloid formation started at his toes. Non-operated toes developed keloids as well, which was possibly related to nail bed irritation, and he had also a skin lesion on his right sole. The keloids increased with time, and after a biopsy was taken rapid growth was noted. He had congenital mildly decreased mobility of his fingers, showing in only faint distal flexion creases of all fingers, but initially no keloid formation at his hands. Radiological studies failed to show bony abnormalities of the hands. At 5 years reduced vision was first noticed. At 7 years, an aggressive pterygium was diagnosed on the right eye, starting from the nasal side and spreading over the cornea. A year later a similar pterygium was noticed on the left eye. At 9 years, he underwent pterygium excision in both eyes, in the left eye Mitomycin C was applied, but the pterygia recurred. Repeated surgery on the right eye was performed but without success. Subsequently, he developed a right-sided symblepharon. At 18 years a keratoprosthesis was implanted in the right eye, with initial success and regain of some visual acuity, but subsequent loss of vision due to dislocation of the keratoprosthesis to the interior of the eye. He has subsequently developed phthisis in the right eye, and has visual acuity of light perception only. In the left eye visual acuity was 0.2 (Snellen) despite recurrence of the pterygium. The temporal part of the cornea of the left eye is still clear (Fig. 3). The proband developed around 15 years of age darkly pigmented skin lesions on trunk and limbs, which sometimes were confluent but sometimes also disappeared. Clinically the skin changes resembled brown angiokeratomas. At that time hammertoes developed, especially of the right 2nd, 3rd, and 4th toe. The camptodactyly had gradually increased and he developed two small keloids, both after trauma, on a middle finger. At age 19 years he was diagnosed with photosensitive dermatitis in his face needing treatment (methotrexate). On examination at age 19 years the proband was a normally intelligent adolescent, height 167 cm (10th centile) and weight 60 kg (30th centile), and head circumference 57.0 cm (50th centile). He had normal hair, an irregularly formed right eyebrow and blepharophimosis, interpreted to be secondary to the earlier surgery (Fig. 1). There were tongues of conjunctival tissue invading the cornea in both eyes, in the right eye covering the whole cornea (Fig. 2), narrow nasal bridge, prominent nose, normal teeth, somewhat high palate, and pits of the posterior helices. He had a normal trunk with mildly increased fat deposits, a thoracic kypho-
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. Face of the proband. Note the narrow nasal bridge and prominent nose.
sis, and normal male genitalia. There was mild hyperhidrosis of face and trunk. Mobility in shoulders and elbows was normal, and hands showed camptodactyly of all fingers. There were small keloids on the middle finger (Fig. 3a). There were only faint flexion creases visible over the distal interphalangeal joints. Mobility in hips and knees was normal. He had hammertoes, more marked on the right side, shortened distal phalanges of the halluces, and bluish discolored keloid tissue on the dorsum of both halluces with some spreading to the dorsum of the feet (Fig. 3b).
UPDATE OF HAUGEN AND BERTELSEN REPORT The family consists of an affected mother (proband) and two affected sons. The parents of the proband had reportedly normal eyes and no keloids. At 2 years ingrowth of scar tissue was observed in both eyes of the proband. Despite surgery the ingrowth progressed and became confluent when she was 8 years of age. From 20 years on she developed keloid-like scars on the flexor side of the fingers causing flexion contractures (Fig. 4a). In her sixties she quite abruptly developed large granuloma-annulare-like eczemas on the posterior aspect of both upper arms. In one of these lesions a sarcoma developed that was successfully treated. The number of cutaneous fibromas increased over the years, especially on the central face, trunk, and extremities. At 73 years she developed an adenocarcinoma of the endometrium, and she died at age 75 years. The oldest son of the proband presented with progressive, superficial grayish corneal opacities in the left eye at 1 year of age and in the right eye at 2 years. At 3 years multiple tongue-like ingrowths approached the center of the corneas (Fig. 4b). Surgical interventions in the right eye were unsuccessful. In his second decade he developed multiple broad-based fibromas on his trunk and neck. At 21 years he developed keloids on his fingers but these were less pronounced compared to those in his mother and brother. At 35 years keloids developed on his halluces (Fig. 4a). The youngest son of the proband had normal eyes until the age of six when thin, grey-white tissue became apparent at the upper temporal limbal region of the right eye. The changes progressed slowly and at 18 years of age covered the whole cornea. The left eye
ABARCA ET AL.
2903
FIG. 2. Eyes of the proband at 19 year of age. Note phthisic right eye (axial length 16mm), extensive scarring due to conjunctival ingrowth over the cornea and previous surgery. The symblepharon of the lower eyelid is secondary to surgery. The left eye (23 mm) shows conjunctival ingrowth nasally and superiorly; the temporal part is relatively spared.
FIG. 3. a. Right hand of the proband and detail of left middle finger. Note the camptodactyly and only faint distal interphalangeal flexion creases. The left middle finger has two small keloids both as results of minor trauma. Fig. 3b. Feet of the proband. Note extensive keloid formation. The keloids on both halluces appeared after surgery for ingrown nails. The keloids on the other toes apparently developed spontaneously.
2904
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 4. a. Distal limbs of family reported by Haugen and Bertelsen [1998]. Left panel: Large keloids on the fingers of the proband (mother) causing syndactyly and restricted movements of especially the index and middle finger, and extending from the back of the fingers to the distal back of the hands. Middle panel: Keloids on the plantar side of the halluces of the eldest son. Right panel: Keloids on the right hand of the youngest son, ending just proximal to the nail bed. Fig. 4b. Eyes of family members reported by Haugen and Bertelsen [1998]. Left panel: The un-operated left eye of the eldest son, showing vascularized tissue covering the cornea completely. Right panel: The left eye of the youngest son showing conjunctival ingrowth on the cornea resembling pterygium.
was unaffected until the age of 20, when similar changes appeared, and in less than four years the optic axis was covered (Fig. 4b). At 15 years slowly progressive and bilaterally symmetric keloids developed on the third, fourth, and fifth fingers covering the dorsal and lateral aspect of the distal phalanges (Fig. 4a). At 28 years keloids arose on the plantar side of both halluces. In addition he developed erythema in the face, and multiple fibromas in his face, neck, shoulders, and back.
DISCUSSION We report on a single individual who has aggressive, early ocular pterygium-like formation with an unusual progression and lack of response to treatment. In addition he has early onset keloid formation on all distal limbs. These manifestations resemble the manifestations described in the three members of a Norwegian family to a great extent (Table I). The present proband showed camptodactyly of hands and feet from early on. Marked camptodactyly of hands were seen in the proband of the Norwegian family, but this was secondary to the extensive keloid formation on the ventral side of her fingers. The present proband has an increased thoracic kyphosis and truncal fat deposits, which were not evident in the Norwegian family. As the major findings in the proband are very similar to the findings in the family described by Haugen and Bertelsen, it seems likely they have the same entity. We suggest
naming the entity ocular pterygium – digital keloid dysplasia, as there are ocular pterygia, keloids on the digits, and the early onset, the continuous progression during life and histological findings fit a dysplasia. Booth and Hodgkins [2006] provided an update of a family reported earlier on by Balaji and colleagues [1991]. In the first report the family was reported to have Ebstein anomaly (displacement of the septal and posterior tricuspid valve leaflets) and restricted finger and toe movements [Balaji et al., 1991]. The update described that one member had ingrowth of fibrous tissue in the cornea on one side and multiple keloids on trunk and limbs [Booth and Hodgkins, 2006]. It was stated that by history several other family members had multiple keloids as well. It remains uncertain whether this family has ocular pterygium-digital dysplasia, due to the presence of eye manifestations in only one of multiple affected members, presence of keloids also on the trunk, and presence of Ebstein anomaly. A pterygium is a common fibrovascular dysplasia affecting the bulbar conjunctiva, more frequently located on the nasal than temporal limbus. In addition to discomfort it can give rise to visual problems if it crosses the pupillary axis. In peri-equatorial countries and in high altitude regions a high incidence of pterygia is seen. Pterygia are assumed to be caused by high exposure to ultraviolet light. Additional risk factors include family history, increasing age, and male gender. Certain groups, such as outdoor workers, have an
ABARCA ET AL.
2905
TABLE I. Main Characteristics in the Present Proband Compared to The Updated Findings Reported by Haugen and Bertelsen [1998] and to Penttinen Syndrome. Penttinen syndromea
Haugen and Bertelsen, 1998 Cognition Growth (centile) Ocular pterygia Age diagnosis Progression Age 1st surgery Keloid (age) Hands Feet Other Thin, translucent skin Abnormal skin pigmentation Abnormal hair pigmentation Acro-osteolysis Short, broad digits Camptodactyly Fingers Toes Face Hair Nasal bridge (Pre)maxilla Nose Thin upper Vermilion Hyperkyphosis Lipodystrophy Other a
Proband Nl 167 cm (P10) bilat 7yr þþ 9yr 4yr þ þþ þ
P1 (Mother) Nl 175 cm (P90) bilat 2yr þþ 4yr 20yr þþ right arm
P2 (son) Nl 170 cm (P15) bilat 1yr þþ 3yr 22yr þ þ þ
P3 (son) Nl 173 cm (P25) bilat 6yr þþ 23yr 15yr þ þ þ
þ þ
þþ
nl narrow nl prominent þ (trunkal fat deposits)
nl multiple fibromas
P1 Nl P50–75
P2 Nl >3SD
P3 Nl 3SD
bilat 9yr ? ?
2yr þ þ elbows, knees þ þ þ þ
bilat 9yr ? ? (3yr) þ þ buttocks þ ? þ þ
þþ
þþ
þþ
nl
nl
sparse broad retracted þ þ
sparse retracted þ þ þ
sparse retracted þ þ þ
multiple fibromas
multiple fibromas
bifid uvula corneal clouding
wide fontanel
craniosynostosis Epilepsy VSD
þ ? þ þ
P1: Penttinen et al., 1997; P2 and P3: Zufferey et al., 2012.
increased incidence to develop pterygia [Liu et al., 2013]. The prevalence of pterygium in Peru has been described as high as 31%. However, in less than 1% of the cases the pterygium extended more than halfway to the center of the cornea and no patients below 20 years of age were described [Rojas and Ma´laga, 1986]. Since the family of the proband has several risk factors for developing pterygium (they live at a high altitude and are outdoor workers), pterygium development is not unexpected in early adulthood, which is the case in the affected family members except the proband. In addition, the natural history in the other family members is as expected for normal pterygium development and different from the course in the proband. Therefore it is unlikely that pterygium development in family members is causally related to the aggressive conjunctival ingrowth seen in the proband. Pterygium formation in children is rare and can in most cases be managed conservatively [Monga et al., 2012]. One family in which aggressive pterygium was
present in three second degree family members, of which two developed ocular changes in childhood (at 6 and 4 years, respectively) has been described. No extraocular signs or symptoms were reported, in particular not with respect to the skin [Islam and Wagoner, 2001]. Another main finding in the present patient is the keloid formation at the distal limbs. There are only a limited number of Mendelian entities that go along with keloid formation. Some of the connective tissue disorders such as Ehlers-Danlos syndrome type IV [Burk et al., 2007] and lateral meningocele syndrome [Chen et al., 2005] can show keloid formation. Goeminne syndrome is characterized by a progressive torticollis, kyphosis, pectus formation, umbilical herniae, varicose veins, normal intelligence, and keloids on trunk and limbs, including hands [Fryns and Gevers, 2003], and this condition may in fact also be a connective tissue disorder. One of us (RCH) has seen several males and females
2906 with a phenotype that resembles frontometaphyseal dysplasia but without detectable Filamin A mutations, who had numerous rounded keloids widely spread over their body. The most frequently occurring syndrome that goes along with keloid formation in a significant percentage of patients is Rubinstein-Taybi syndrome [Hennekam, 2006]. A recent study showed that 24% of all Rubinstein-Taybi patients develop keloids [Van de Kar et al., in press]. Keloids in this entity are located on upper thorax, shoulders and upper arms, and rarely elsewhere. Myhre syndrome is characterized by intellectual disability, short stature with a stocky body build, hearing loss, an unusual face, and keloids can occur in the upper airways (nose; larynx) [McGowan et al., 2011]. In oculo-ectodermal syndrome macrocephaly, areas of aplasia cutis of the scalp, epibulbar dermoids, and areas of hyperpigmentation of the skin can go along with keloid formation as well [Evers et al., 1994]. Several families have been described with a phenotype that resembles Bardet-Biedl syndrome without the distal limb anomalies but with deafness, cataract, and keloid formation as additional manifestations [Boor et al., 1993]. Heyen and co-workers reported on several individuals from a single family who had a large optic cupto-disc ratio, camptodactyly and keloid formation on trunk or proximal limbs [Heyen et al., 2008]. Finally, keloid formation has rarely been described in chromosome imbalances such as Turner syndrome and deletions of the terminal part of chromosome 19p [Archer et al., 2005], and in a small number of case reports [Leung et al., 1988; Coffin, 1990; Anandan et al., 2008]. In none of the above entities progressive conjunctival ingrowth on the cornea was seen, and only very infrequently keloids develop on their hands and feet. There is a single entity in which ocular pterygia have been reported together with keloids on the distal limbs, i.e. Penttinen syndrome [Penttinen et al., 1997; Zufferey et al., 2012]. The three patients reported with this entity may have ocular pterygia that arise at a very young age as in ocular pterygium-digital keloid dysplasia, and may also have keloid formation on the back of the hands and feet (Table I). However, in Penttinen syndrome the affected individuals may show somatic overgrowth, facial characteristics (sparse hair, retracted maxilla and pre-maxilla, and thin upper vermillion), an unusual thin and translucent skin, progressive acro-osteolysis, progressive lipodystrophy, and short and broad digits, especially thumbs and halluces. We concur with Zufferey and co-workers [2013] that despite the resemblances the differences are sufficient to discern the two entities. We conclude that the present patient resembles the family reported by Haugen and Bertelsen [1998] but not any other entity, The occurrence of the syndrome in two generations, both sexes, and absence of consanguinity all point to an autosomal dominant pattern of inheritance. The cause is unknown. We have initiated a molecular study using next generation sequencing techniques in order to detect the gene causing this entity.
ACKNOWLEDGMENTS We thank the family for their participation in this study. We thank Eyvind Rødahl for useful discussions and Marte Emilie Sandvik Haaland and Lisbet Sviland for professional assistance. This study was supported by grants from the Western Norway Regional Health
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Authority (911466 and 911688 to C.B). None of the authors have any conflicts of interests.
REFERENCES Anandan V, Parveen B, Prabhavathy D, Priyavarthini V. 2008. Adams Oliver syndrome—A variant. Int J Dermatol 47:1260–1262. Archer HL, Gupta S, Enoch S, Thompson P, Rowbottom A, Chua I, Warren S, Johnson D, Ledbetter DH, Lese-Martin C, Williams P, Pilz DT. 2005. Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13.3-pter. Am J Med Genet 136A:38–44. Balaji S, Dennis NR, Keeton BR. 1991. Familial Ebstein anomaly: A report of six cases in two generations associated with mild skeletal abnormalities. Br Heart J 66:26–28. Boor R, Herwig J, Schrezenmeir J, Pontz BF, Schonberger W. 1993. Familial insulin resistant diabetes associated with acanthosis nigricans, polycystic ovaries, hypogonadism, pigmentary retinopathy, labyrinthine deafness, and mental retardation. Am J Med Genet 45:649–653. Booth AJ, Hodgkins PR. 2006. Pseudopterygium arising in a patient with multiple keloids. J Pediatr Ophthalmol Strabis 43:49–51. Burk CJ, Aber C, Connelly EA. 2007. Ehlers-Danlos syndrome type IV: Keloidal plaques of the lower extremities, amniotic bands, limb deformities, and a new mutation. J Am Acad Dermatol 56 (Suppl 2): S53–S54. Chen KM, Bird L, Barnes P, Barth R, Hudgins L. 2005. Lateral meningocele syndrome: Vertical transmission and expansion of the phenotype. Am J Med Genet 133A:115–121. Coffin GS. 1990. Developmental retardation with unusual facies, arthritis, and hearing impairment. Dysmorph Clin Genet 4:103–109. Coroneo MT, Chui JJY. 2013. Pterygium In: Holland EJ, Mannis MJ, Barry Lee W, Ocular surface disease:Cornea, conjuntiva and tear film. Philadelphia: Elsevier Sauders. p. 125–144. Evers MEJW, Dijkman-Neerincx RHM, Hamel BCJ. 1994. Oculo-ectodermal syndrome: A new case. Am J Med Genet 53:378–379. Fryns JP, Gevers D. 2003. Goeminne syndrome (OMIM 314300): Another male patient 30 years later. Genet Counsel 14:109–111. Haugen OH, Bertelsen T. 1998. A new hereditary conjunctivo-corneal dystrophy associated with dermal keloid formation. Acta Ophthalmol Scand 76:461–465. Hennekam RCM. 2006. Rubinstein-Taybi syndrome. Eur J Hum Genet 14:981–985. Heyen CA, Delk PR, Bull MJ, Weaver DD. 2008. A report of an apparent new genetic syndrome consisting of joint contractures, keloids, large optic cup-to-disc ratio and renal stones. Am J Med Genet 146A:3120– 3125. Islam SI, Wagoner MD. 2001. Pterygium in young members of one family. Cornea 20:708–710. Leung RSC, Beer WE, Mehta HK. 1988. Aplasia cutis congenita presenting as a familial triad of atrophic alopecia, ocular defects and a peculiar scarring tendency of the skin. Br J Dermatol 118:715–720. Liu L, Wu J, Geng J, Yuan Z, Huang D. 2013. Geographical prevalence and risk factors for pterygium: A systematic review and meta-analysis. BMJ Open 3:e003787. McGowan R, Gulati R, McHenry P, Cooke A, Butler S, Keng WT, Murday V, Whiteford M, Dikkers FG, Sikkema-Raddatz B, van Essen T, Tolmie J. 2011. Clinical features and respiratory complications in myhre syndrome. Eur J Med Genet 54:553–559.
ABARCA ET AL.
2907
Monga S, Gupta A, Kekunnava R, Goyal S, Vemuganti GK, Sachdeva V. 2012. Childhood pterygium; a descriptive study of 19 cases presented to a tertiary eye care center. Am J Ophthalmol 154:859–864.
Van de Kar A, Houge G, Shaw AC, Van Belzen MJ, Peters DJM, Hennekam RC. Keloids in Rubinstein-Taybi syndrome: A clinical study. Br J Dermatol. In press.
Penttinen M, Niemi KM, Vinkka-Puhakka H, Johansson R, Aula P. 1997. New progeroid disorder. Am J Med Genet 69:182–187.
Zufferey F, Hadj-Rabia S, De Sandre-Giovannoli A, Dufier JL, Leheup B, Schweitze C, Bodemer C, Cormier-Daire V, Le Merrer M. 2012. Acroocteolysis, keloid like-lesions, distinctive facial features, and overgrowth: Two newly recognized patients with premature aging syndrome, penttinen type. Am J Med Genet 161A:1786–1791.
Rojas JR, Ma´laga H. 1986. Pterygium in Lima, Peru. Ann Ophthalmol 18:147–149.
