RESEARCH LETTER
Report of a Patient With Temple–Baraitser Syndrome Gozde Yesil,1* Serhat Guler,2 Adnan Yuksel,3 and Yasemin Alanay4 1
Department of Medical Genetics, Bezmialem Vakif University Medicine, Istanbul, Fatih, Turkey
2
Department of Pediatric Neurology, Bezmialem Vakif University Medicine, Istanbul, Fatih, Turkey
3
Department of Medical Genetics, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Fatih, Turkey Department of Pediatric Genetics, Acibadem University of Medicine, Istanbul, Fatih, Turkey
4
Manuscript Received: 21 July 2013; Manuscript Accepted: 3 October 2013
TO THE EDITOR: Temple–Baraitser syndrome (TBS) [OMIM: %611816] is possibly an under recognized condition in which abnormal thumb and great toes accompany severe intellectual disability. The condition was initially described in 1992 in a patient with severe intellectual disability and absence/hypoplasia of the thumb and hallux [Temple and Baraitser, 1991]. Since then, three additional patients have been reported [Gabbet et al., 2008; Jacquinet et al., 2010]. The consistent pattern shared by all patients in the literature is severe intellectual disability and a motor deficit with minor dysmorphic features and ray abnormalities like small/absent nails with elongation of thumbs and halluces. Array CGH in two and microarray in one showed normal results [Jaquinet et al., 2010]. A single gene defect, yet to be discovered is hypothesized to be responsible for this relatively rare condition. We report on an additional patient; the first child of an unrelated couple, born at term by caesarian section following an uncomplicated pregnancy. His birth weight 3,600 g (50p) and height 52 cm (50–75p) were normal. The family history was unremarkable. Delay in early developmental milestones was the initial concern. He sat without support at age 1 year. He was referred for psychomotor developmental delay at the age of 3 years and 7 months. His weight, height, head circumference were within normal ranges. He had no speech and eye contact was poor. Mild dysmorphic facial findings; bilateral epicanthal folds, ears with thick helices, downslanting palpebral fissures, thick and everted vermilion of the lower lip and underdeveloped nasolabial folds leading to a myopathic facial appearance were recognized at examination (Fig. 1A,B). Short neck, widely spaced nipples, micropenis, a large mongolian spot on the lumbosacral area, and tapering fingers were also noted. Both thumbs were proximally placed with short distal phalanges and small nails. The halluces were both elongated and relatively narrow and the nails were also small. Radiography of hands and feet showed a spindle shaped distal phalangeal ossification in both thumbs and hypo/aplasia in halluces. There is an increased lucency on the center of bones on distal phalanges of both thumbs and halluces (Fig. 2A and B). The patient received valproic acid after an episode of febrile convulsion at the age of three. EEG showed focal spike wave discharges on left temporal, parietal, and right parietooccipital region. Cerebral MRI revealed mild frontotemporal atrophy. Atrial
Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Yesil G, Guler S, Yuksel A, Alanay Y. 2014. Report of a patient with Temple–Baraitser syndrome. Am J Med Genet Part A 164A:848–851.
septal defect and mild pulmonary stenosis were present in echocardiographic investigation. Transferrin isoelectric focusing revealed no signs of congenital disorders of glycosylation. Endocrine tests performed for micropenis, including sex hormones were at normal ranges. Peripheral blood karyotype revealed 47, XXY. Array CGH analysis was performed as his findings could not be solely explained by Klinefelter syndrome. 60K Array CGH did not show any additional copy number variations. The diagnosis of Temple–Baraitser syndrome was established based on clinical and radiographic findings. Table I summarizes clinical findings in the previously reported TBS patients in comparison to the present report. The facial resemblance with myopathic appearance, mild hypertelorism, broad nasal bridge, short columella, long philtrum and down turned corners of the mouth is striking [Temple and Baraitser, 1991; Gabbet et al., 2008; Jacquinet et al., 2010]. Presence of epicanthal folds, previously reported in two other patients is noteworthy [Gabbet et al., 2008; Jacquinet et al., 2010]. Presence of pulmonary valve stenosis and atrial septal defect in our patient might also expand the phenotype. We considered the presence of micropenis as a consequence of 47,XXY karyotype, probably not a part of the syndrome. The toenails tend to be more affected than then thumbs. However hypoplasia rather than aplasia of the hallux
Correspondence to: Gozde Yesil, M.D., Bezmialem Vakif University Medicine, Department of Medical Genetics, Vatan Cad.,34093 Fatih, Istanbul, Turkey. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 19 December 2013 DOI 10.1002/ajmg.a.36344
848
YESIL ET AL.
FIG. 1. Dysmorphic features of the patient. A: myopathic appearance, epicanthal folds, hypertelorism, broad nasal bridge, short columella, long philtrum and downturned corners of the mouth. B: Short neck, low posterior hairline, thick ear helix, large ear lobe, chubby cheeks.
FIG. 2. Extremity findings. A: Right thumb, proximally placed with short distal phalanx and small nail. B: Left hallux, elongated and relatively narrow with small nail. C, D: Radiography of hands and feet showing a spindle like distal phalangeal ossification in thumbs and hypo/aplasia of distal phalanges on both halluces. Note, increased lucency on the center of bones on distal phalanges of both thumbs and halluces.
849
þ þ 7 years þ Normal þ nd þ þ þ þ þ þ nd
þ nd 2 years þ nd þ þ þ þ þ þ þ þ þ þ nd nd nd nd
þ nd 4 years þ Global cerebral atrophy nd nd nd þ þ þ nd nd nd nd nd nd
GER nd nd
Hypoplasia Absence þ þ þ þ
Hypoplasia Absence þ þ þ þ þ
Absence Absence nd nd þ þ
Jacquinet [2008] 610/12
Gabbet et al. [2008] 44/12
Temple and Baraitser [1991] 35/12
GER, gastroeosephageal reflux; PS, pulmonary stenosis; ASD, atrial septal defect; nd, not documented.
Clinical findings Age Consanguinity Limbs Absence/hypoplasia of thumb nail Absence/hypoplasia of halluxnail Broad thumbs terminally Thumbs; long, proximally set Adductus deformity of distal thumb Pseudoepiphysis of the distal phalanges Hypoplasia of other distal phalanges Neurologic Intellectual disability Poor visual contact/autistic behavior Seziures starting age Hypotonia/Motor retardation MRI findings Dysmorphic features Coarse thick hair Myopathic face Flat forehead Mild hypertelorism Epichantal folds Broad depressed nasal bridge Short columella Long philtrum Thick vermillion border of upper lip Broad mouth with downturned corners Inverted nipples Systemic manifestations Gastrointestinal symptoms Small genitalia/endocrine anomalies Cardiovascular system þ þ þ þ þ þ þ þ þ þ þ Constipation þ PS, ASD
nd nd
þ þ 3 years þ Mild frontotemporal atrophy
Hypoplasia þ þ þ þ þ þ
Present Patient 37/12
þ nd þ þ (Chinese) þ nd þ þ þ nd
þ þ Normal
Hypoplasia/absence Absence þ þ þ þ þ
Jacquinet [2008] 11/12
TABLE I. Comparison of Clinical Features of Previously Reported Temple-Baraitser Patients
3/5 1/1 1/1
4/4 4/4 4/4 1/5
2/2 5/5 3/5 4/5
4/2
4/5 3/3 4/5 5/5 2/4
5/5 5/5 4/5 4/4 4/4 5/5 4/5
0/5
Number of affected patients
850 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
YESIL ET AL. nails were only seen in our patient while the others had total absence of the nail. Only one patient had unilateral aplasia of the thumb nail [Jacquinet et al., 2010]. Radiographic images demonstrating aplasia/hypoplasia on all phalanges and pesudoepiphyses of thumbs and toes are consistent in all patients [Temple and Baraitser, 1991; Gabbet et al., 2008; Jacquinet et al., 2010]. Presence of a proximally implanted and distally broadened thumb and long hallux is also a common feature [Gabbet et al., 2008; Jacquinet et al., 2010]. The translucent areas on distal phalanges resembling extra epiphyses are shown in Figure 2. Severe hypotonia, motor delay and severe intellectual deficiency are constant neurologic findings. Epilepsy diagnosed beyond infancy is present in all except one patient who was 12 months old at diagnosis. Despite absence of clinical seizures he was receiving antiepileptic therapy for disorganized EEG findings following a febrile seizure. The MRI findings were normal in three patients [Gabbet et al., 2008; Jacquinet et al., 2010]. The first patient reported by Temple and Baraitser manifested a global cerebral atrophy in CT scans [Temple and Baraitser, 1991]. Our patient had also mild atrophy spanning through frontal to temporal area. There are only a limited number of syndromes with features overlapping TBS. DOOR syndrome [OMIM, 220500] is an acronym for deafness, onychodystrophy, osteodystrophy, and “mental retardation.” Deafness is profound and present from infancy. Most patients have coarse facial features with broad nasal bridge, anteverted nares, everted vermilion of the lower lip, and high palate. Ophthalmologic abnormalities including optic atrophy and blindness, high myopia, and iris hypoplasia have been reported [James et al., 2007]. Other neurologic abnormalities included neonatal hypotonia, seizures, and peripheral neuropathy. Less common findings included dental, renal, and cardiac anomalies. The disorder follows a progressive course and 32% die in early childhood from seizures or respiratory distress. Autosomal recessive mode of inheritance has been suggested, while genetic etiology is yet unknown. Despite similarities, the consistent finding of hearing loss has not been detected in TBS patients so far. The facial features are rather coarse than myopathic and the natural history is rather stable compared with the progressive deterioration in DOOR patients.
851 Another rare entity with nail abnormalities and developmental delay is Lynch–Bushby syndrome [Cantwell, 1975; Lynch et al., 1997]. The cardinal findings in this rare autosomal dominant syndrome are choreoathetosis, epilepsy, absence of toe and thumb nails and mild intellectual deficiency. Despite severe motor delay, movement problems have not developed in TBS patients. These phenotypically similar conditions might in fact share a common genetic etiology with variable expression or be part of a common cellular pathway. In conclusion, TBS is a rare small nail syndrome with mild dysmorphic features, small or absent nail, epilepsy with severe motor deficit and intellectual delay. The absence of affected siblings with normal parents in all published cases and our family supports previous observations suggesting a possible de novo dominant inheritance. The underlying molecular defect is yet to be identified. Molecular studies for gene identification are underway.
REFERENCES Cantwell RJ. 1975. Congenital sensory neural deafness associated with onycho-osteodystrophy and mental retardation (D.O.O.R. syndrome). Hum Genet 26:261–265. Gabbett MT, Clark RC, McGaughran JM. 2008. A second case of severe mental retardation and absent nails of hallux and pollex (Temple–Baraitser syndrome). Am J Med Genet Part A 146A:450– 452. Jacquinet A, Gerard M, Gabbett MT, Rausin L, Misson J-P, Menten B, Mortier G, VanMaldergem L, Verloes A, Debray F-G. 2010. Temple– Baraitser syndrome: A rare and possibly unrecognized condition. Am J Med Genet Part A 152A:2322–2326. James AW, Miranda SG, Culver K, Hall BD, Golabi M. 2007. DOOR syndrome: clinical report, literature review and discussion of natural history. Am J Med Genet Part A 143A:2821–2831. Lynch SA, Gardner-Medwin D, Burn J, Bushby KM. 1997. Absent nails, kinesogenic choreoathetosis, epilepsy and developmental delay; a new autosomal dominant disorder? Clin Dysmorphol. 6:133– 138. Temple IK, Baraitser M. 1991. Severe mental retardation and absent nails of hallux and pollex. Am J Med Genet 41:173–175.
Report of a Patient With Temple–Baraitser Syndrome Gozde Yesil,1* Serhat Guler,2 Adnan Yuksel,3 and Yasemin Alanay4 1
Department of Medical Genetics, Bezmialem Vakif University Medicine, Istanbul, Fatih, Turkey
2
Department of Pediatric Neurology, Bezmialem Vakif University Medicine, Istanbul, Fatih, Turkey
3
Department of Medical Genetics, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Fatih, Turkey Department of Pediatric Genetics, Acibadem University of Medicine, Istanbul, Fatih, Turkey
4
Manuscript Received: 21 July 2013; Manuscript Accepted: 3 October 2013
TO THE EDITOR: Temple–Baraitser syndrome (TBS) [OMIM: %611816] is possibly an under recognized condition in which abnormal thumb and great toes accompany severe intellectual disability. The condition was initially described in 1992 in a patient with severe intellectual disability and absence/hypoplasia of the thumb and hallux [Temple and Baraitser, 1991]. Since then, three additional patients have been reported [Gabbet et al., 2008; Jacquinet et al., 2010]. The consistent pattern shared by all patients in the literature is severe intellectual disability and a motor deficit with minor dysmorphic features and ray abnormalities like small/absent nails with elongation of thumbs and halluces. Array CGH in two and microarray in one showed normal results [Jaquinet et al., 2010]. A single gene defect, yet to be discovered is hypothesized to be responsible for this relatively rare condition. We report on an additional patient; the first child of an unrelated couple, born at term by caesarian section following an uncomplicated pregnancy. His birth weight 3,600 g (50p) and height 52 cm (50–75p) were normal. The family history was unremarkable. Delay in early developmental milestones was the initial concern. He sat without support at age 1 year. He was referred for psychomotor developmental delay at the age of 3 years and 7 months. His weight, height, head circumference were within normal ranges. He had no speech and eye contact was poor. Mild dysmorphic facial findings; bilateral epicanthal folds, ears with thick helices, downslanting palpebral fissures, thick and everted vermilion of the lower lip and underdeveloped nasolabial folds leading to a myopathic facial appearance were recognized at examination (Fig. 1A,B). Short neck, widely spaced nipples, micropenis, a large mongolian spot on the lumbosacral area, and tapering fingers were also noted. Both thumbs were proximally placed with short distal phalanges and small nails. The halluces were both elongated and relatively narrow and the nails were also small. Radiography of hands and feet showed a spindle shaped distal phalangeal ossification in both thumbs and hypo/aplasia in halluces. There is an increased lucency on the center of bones on distal phalanges of both thumbs and halluces (Fig. 2A and B). The patient received valproic acid after an episode of febrile convulsion at the age of three. EEG showed focal spike wave discharges on left temporal, parietal, and right parietooccipital region. Cerebral MRI revealed mild frontotemporal atrophy. Atrial
Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Yesil G, Guler S, Yuksel A, Alanay Y. 2014. Report of a patient with Temple–Baraitser syndrome. Am J Med Genet Part A 164A:848–851.
septal defect and mild pulmonary stenosis were present in echocardiographic investigation. Transferrin isoelectric focusing revealed no signs of congenital disorders of glycosylation. Endocrine tests performed for micropenis, including sex hormones were at normal ranges. Peripheral blood karyotype revealed 47, XXY. Array CGH analysis was performed as his findings could not be solely explained by Klinefelter syndrome. 60K Array CGH did not show any additional copy number variations. The diagnosis of Temple–Baraitser syndrome was established based on clinical and radiographic findings. Table I summarizes clinical findings in the previously reported TBS patients in comparison to the present report. The facial resemblance with myopathic appearance, mild hypertelorism, broad nasal bridge, short columella, long philtrum and down turned corners of the mouth is striking [Temple and Baraitser, 1991; Gabbet et al., 2008; Jacquinet et al., 2010]. Presence of epicanthal folds, previously reported in two other patients is noteworthy [Gabbet et al., 2008; Jacquinet et al., 2010]. Presence of pulmonary valve stenosis and atrial septal defect in our patient might also expand the phenotype. We considered the presence of micropenis as a consequence of 47,XXY karyotype, probably not a part of the syndrome. The toenails tend to be more affected than then thumbs. However hypoplasia rather than aplasia of the hallux
Correspondence to: Gozde Yesil, M.D., Bezmialem Vakif University Medicine, Department of Medical Genetics, Vatan Cad.,34093 Fatih, Istanbul, Turkey. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 19 December 2013 DOI 10.1002/ajmg.a.36344
848
YESIL ET AL.
FIG. 1. Dysmorphic features of the patient. A: myopathic appearance, epicanthal folds, hypertelorism, broad nasal bridge, short columella, long philtrum and downturned corners of the mouth. B: Short neck, low posterior hairline, thick ear helix, large ear lobe, chubby cheeks.
FIG. 2. Extremity findings. A: Right thumb, proximally placed with short distal phalanx and small nail. B: Left hallux, elongated and relatively narrow with small nail. C, D: Radiography of hands and feet showing a spindle like distal phalangeal ossification in thumbs and hypo/aplasia of distal phalanges on both halluces. Note, increased lucency on the center of bones on distal phalanges of both thumbs and halluces.
849
þ þ 7 years þ Normal þ nd þ þ þ þ þ þ nd
þ nd 2 years þ nd þ þ þ þ þ þ þ þ þ þ nd nd nd nd
þ nd 4 years þ Global cerebral atrophy nd nd nd þ þ þ nd nd nd nd nd nd
GER nd nd
Hypoplasia Absence þ þ þ þ
Hypoplasia Absence þ þ þ þ þ
Absence Absence nd nd þ þ
Jacquinet [2008] 610/12
Gabbet et al. [2008] 44/12
Temple and Baraitser [1991] 35/12
GER, gastroeosephageal reflux; PS, pulmonary stenosis; ASD, atrial septal defect; nd, not documented.
Clinical findings Age Consanguinity Limbs Absence/hypoplasia of thumb nail Absence/hypoplasia of halluxnail Broad thumbs terminally Thumbs; long, proximally set Adductus deformity of distal thumb Pseudoepiphysis of the distal phalanges Hypoplasia of other distal phalanges Neurologic Intellectual disability Poor visual contact/autistic behavior Seziures starting age Hypotonia/Motor retardation MRI findings Dysmorphic features Coarse thick hair Myopathic face Flat forehead Mild hypertelorism Epichantal folds Broad depressed nasal bridge Short columella Long philtrum Thick vermillion border of upper lip Broad mouth with downturned corners Inverted nipples Systemic manifestations Gastrointestinal symptoms Small genitalia/endocrine anomalies Cardiovascular system þ þ þ þ þ þ þ þ þ þ þ Constipation þ PS, ASD
nd nd
þ þ 3 years þ Mild frontotemporal atrophy
Hypoplasia þ þ þ þ þ þ
Present Patient 37/12
þ nd þ þ (Chinese) þ nd þ þ þ nd
þ þ Normal
Hypoplasia/absence Absence þ þ þ þ þ
Jacquinet [2008] 11/12
TABLE I. Comparison of Clinical Features of Previously Reported Temple-Baraitser Patients
3/5 1/1 1/1
4/4 4/4 4/4 1/5
2/2 5/5 3/5 4/5
4/2
4/5 3/3 4/5 5/5 2/4
5/5 5/5 4/5 4/4 4/4 5/5 4/5
0/5
Number of affected patients
850 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
YESIL ET AL. nails were only seen in our patient while the others had total absence of the nail. Only one patient had unilateral aplasia of the thumb nail [Jacquinet et al., 2010]. Radiographic images demonstrating aplasia/hypoplasia on all phalanges and pesudoepiphyses of thumbs and toes are consistent in all patients [Temple and Baraitser, 1991; Gabbet et al., 2008; Jacquinet et al., 2010]. Presence of a proximally implanted and distally broadened thumb and long hallux is also a common feature [Gabbet et al., 2008; Jacquinet et al., 2010]. The translucent areas on distal phalanges resembling extra epiphyses are shown in Figure 2. Severe hypotonia, motor delay and severe intellectual deficiency are constant neurologic findings. Epilepsy diagnosed beyond infancy is present in all except one patient who was 12 months old at diagnosis. Despite absence of clinical seizures he was receiving antiepileptic therapy for disorganized EEG findings following a febrile seizure. The MRI findings were normal in three patients [Gabbet et al., 2008; Jacquinet et al., 2010]. The first patient reported by Temple and Baraitser manifested a global cerebral atrophy in CT scans [Temple and Baraitser, 1991]. Our patient had also mild atrophy spanning through frontal to temporal area. There are only a limited number of syndromes with features overlapping TBS. DOOR syndrome [OMIM, 220500] is an acronym for deafness, onychodystrophy, osteodystrophy, and “mental retardation.” Deafness is profound and present from infancy. Most patients have coarse facial features with broad nasal bridge, anteverted nares, everted vermilion of the lower lip, and high palate. Ophthalmologic abnormalities including optic atrophy and blindness, high myopia, and iris hypoplasia have been reported [James et al., 2007]. Other neurologic abnormalities included neonatal hypotonia, seizures, and peripheral neuropathy. Less common findings included dental, renal, and cardiac anomalies. The disorder follows a progressive course and 32% die in early childhood from seizures or respiratory distress. Autosomal recessive mode of inheritance has been suggested, while genetic etiology is yet unknown. Despite similarities, the consistent finding of hearing loss has not been detected in TBS patients so far. The facial features are rather coarse than myopathic and the natural history is rather stable compared with the progressive deterioration in DOOR patients.
851 Another rare entity with nail abnormalities and developmental delay is Lynch–Bushby syndrome [Cantwell, 1975; Lynch et al., 1997]. The cardinal findings in this rare autosomal dominant syndrome are choreoathetosis, epilepsy, absence of toe and thumb nails and mild intellectual deficiency. Despite severe motor delay, movement problems have not developed in TBS patients. These phenotypically similar conditions might in fact share a common genetic etiology with variable expression or be part of a common cellular pathway. In conclusion, TBS is a rare small nail syndrome with mild dysmorphic features, small or absent nail, epilepsy with severe motor deficit and intellectual delay. The absence of affected siblings with normal parents in all published cases and our family supports previous observations suggesting a possible de novo dominant inheritance. The underlying molecular defect is yet to be identified. Molecular studies for gene identification are underway.
REFERENCES Cantwell RJ. 1975. Congenital sensory neural deafness associated with onycho-osteodystrophy and mental retardation (D.O.O.R. syndrome). Hum Genet 26:261–265. Gabbett MT, Clark RC, McGaughran JM. 2008. A second case of severe mental retardation and absent nails of hallux and pollex (Temple–Baraitser syndrome). Am J Med Genet Part A 146A:450– 452. Jacquinet A, Gerard M, Gabbett MT, Rausin L, Misson J-P, Menten B, Mortier G, VanMaldergem L, Verloes A, Debray F-G. 2010. Temple– Baraitser syndrome: A rare and possibly unrecognized condition. Am J Med Genet Part A 152A:2322–2326. James AW, Miranda SG, Culver K, Hall BD, Golabi M. 2007. DOOR syndrome: clinical report, literature review and discussion of natural history. Am J Med Genet Part A 143A:2821–2831. Lynch SA, Gardner-Medwin D, Burn J, Bushby KM. 1997. Absent nails, kinesogenic choreoathetosis, epilepsy and developmental delay; a new autosomal dominant disorder? Clin Dysmorphol. 6:133– 138. Temple IK, Baraitser M. 1991. Severe mental retardation and absent nails of hallux and pollex. Am J Med Genet 41:173–175.
