Clin Genet 2014: 86: 394–395 Printed in Singapore. All rights reserved
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12290
Letter to the Editor
Mother-to-daughter transmission of Kenny–Caffey syndrome associated with the recurrent, dominant FAM111A mutation p.Arg569His To the Editor: Kenny–Caffey syndrome (KCS) is a rare condition associated with short stature, cortical thickening of tubular bones, delayed closure of the fontanelle, ocular and dental anomalies, and variable low serum calcium. Recently, Unger et al. found that FAM111A is responsible for the autosomal dominant form (type 2; OMIM 127000) (1). Little is known about FAM111A and its function. Its expression is strongly cell-cycle dependent and present in the cytoplasm and nucleus, suggesting that it may be involved in gene transcription (2). The initial paper on KCS was of a mother and son described by Kenny and Linarelli (3), but there have been few other parent-to-child transmissions (4–6). The proband came to medical attention at 4 days of life due to seizure activity secondary to low serum calcium and magnesium levels. She was delivered at 38 weeks gestation as a result of intrauterine growth restriction. Birth weight was −2.5 standard deviation score [SDS – World Health Organisation (WHO) growth charts for Canada] and length was below −4 SDS. Head circumference was within the average range (−1 SDS), with a large anterior fontanelle. Cranial imaging and electroencephalography (EEG) were unremarkable. Initial ionized calcium level was 0.55 (1.15–1.35 mmol/l) and magnesium was 0.50 (0.65–1.05 mmol/l) with a parathyroid hormone value of 0.4 (1.6–9.30 pmol/l). After receiving boluses, values eventually stabilized and she was discharged home on replacement therapy. At 3 years of age, she was able to maintain her calcium levels off replacement, but still required magnesium supplementation. After a gastrointestinal illness, she needed to restart the supplemental calcium and this requirement has continued. Her stature is short (−5 SDS), her fontanelle remains open, but her head growth and development are within the average range. She has frontal bossing and small appearing eyes. She wears glasses and has dental caps for caries. The proband’s mother was 25 years of age at delivery. She was born as part of a dizygous twin pregnancy at term with a birth weight of 1870 g. She had her first hypocalcemic seizure at 6 days of age and was
394
subsequently found to have hypoparathyroidism. She has been on lifelong calcium supplementation, although she has not had consistent control of her levels. Her recent parathyroid hormone measurements have been in the average range. Her other medical issues include hypothyroidism, sensorineural hearing loss, and oligodontia with retention of her primary teeth. She required a modified program in school. On examination, her height is −5 SDS. She does not have a prominent forehead and her head circumference is −4 SDS. The posterior fontanelle remains open. She wears glasses. Radiographs on the proband in the newborn period were reported as unremarkable. When the proband was 3 years of age, X-rays were carried out on her mother that showed the classic findings of KCS (Fig. 1). Radiographs from the proband showed similar, but milder changes. Samples were obtained from the family and the FAM111A gene was analyzed using Sanger sequencing. The c.1706G > A (p.Arg569His) mutation that was identified in 4/5 of the KCS patients reported by Unger et al. (1) was present in the two affected individuals and not in the unaffected maternal grandparents. We report the first molecularly confirmed instance of mother-to-child transmission of KCS. Inheritance from a father to a child has not been described, despite there being an equal sex ratio of affected individuals reported in the literature (7). Hoffman et al. tried to determine the etiology of the subfertility and investigated two males with microorchidism (8). Endocrine studies of the sex hormones showed that levels were within the average range, except for elevations of the follicle-stimulating hormone. Histology of a testis revealed Leydig cell hyperplasia, but otherwise preserved anatomy. Despite these findings, a mechanism for the microorchidism was not determined. There were no comments that the penile size was outside of the average range, although in the allelic condition, osteocraniostenosis (OMIM 602361), micropenis was reported in 4/5 mutation positive males (1). Together, these data suggest that FAM111A may also be important in the development and function of male genitalia.
Letter to the Editor (a)
(c)
(b)
(d)
(e)
(f)
Fig. 1. Radiographs of the proband at 3 years and her mother at age 28 years. (a) Skull film of the proband demonstrating the large fontanelle. (b) Skull of the mother demonstrating osteosclerosis and dental anomalies. (c, d) Lower limbs of the proband showing narrow long bones with mild narrowing of the medullary cavities. (e, f) Pelvis and lower limb of the mother with greater narrowing of the medullary cavities of the tubular bones.
Acknowledgements The authors would like to thank the family for their participation and assistance. Research was supported through the FORGE Canada Consortium with funding provided by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR) and the Ontario Genomics Institute (OGI-049). K. M. B. is supported by a Clinical Investigatorship Award from the CIHR Institute of Genetics.
S.M. Nikkela,b A. Ahmedc A. Smithc J. Marcadierc D.E. Bulmanb,c K.M. Boycotta,b,c a Department of Genetics Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada b University of Ottawa, Ottawa, ON, Canada c Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada References
2. Fine DA, Rozenblatt-Rosen O, Padi M et al. Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor. PLoS Pathog 2012: 8: e1002949. 3. Kenny FM, Linarelli L. Dwarfism and cortical thickening of tubular bones: transient hypocalcemia in a mother and son. Am J Dis Child 1966: 111: 201–207. 4. Sarría A, Toledo F, Toledo J, Vega ML, Lopez S, Bueno M. Diaphysary tubular stenosis (Kenny-Caffey’s syndrome): presentation of four observations. An Esp Pediatr 1980: 13: 373–380. 5. Majewski F, Rosendahl W, Ranke M, Nolte K. The Kenny syndrome a rare type of growth deficiency with tubular stenosis, transient hypoparathyroidism and anomalies of refraction. Eur J Pediatr 1981: 136: 21–30. 6. Enriquez EJ, Toledo F, Bustamante-Cruz M, Cruz GM. Congenital medullary tubular stenosis. A case of Caffey-Kenny syndrome. Acta Orthop Scand 1988: 59: 326–327. 7. Moussaid Y, Griffiths D, Richard B et al. Oral manifestations of patients with Kenny-Caffey syndrome. Eur J Med Genet 2012: 55: 441–445. 8. Hoffman WH, Kovacs K, Li S et al. Kenny-Caffey syndrome and microorchidism. Am J Med Genet 1998: 80: 107–111.
Correspondence: Sarah M. Nikkel Department of Genetics Children’s Hospital of Eastern Ontario 401 Smyth Road, Ottawa ON, Canada Tel.: +1 613 737 7600x2611; fax: +1 613 738 4220; e-mail: [email protected]
1. Unger S, G´orna MW, Le B´echec A et al. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet 2013. Epub 14 May 2013.
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© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12290
Letter to the Editor
Mother-to-daughter transmission of Kenny–Caffey syndrome associated with the recurrent, dominant FAM111A mutation p.Arg569His To the Editor: Kenny–Caffey syndrome (KCS) is a rare condition associated with short stature, cortical thickening of tubular bones, delayed closure of the fontanelle, ocular and dental anomalies, and variable low serum calcium. Recently, Unger et al. found that FAM111A is responsible for the autosomal dominant form (type 2; OMIM 127000) (1). Little is known about FAM111A and its function. Its expression is strongly cell-cycle dependent and present in the cytoplasm and nucleus, suggesting that it may be involved in gene transcription (2). The initial paper on KCS was of a mother and son described by Kenny and Linarelli (3), but there have been few other parent-to-child transmissions (4–6). The proband came to medical attention at 4 days of life due to seizure activity secondary to low serum calcium and magnesium levels. She was delivered at 38 weeks gestation as a result of intrauterine growth restriction. Birth weight was −2.5 standard deviation score [SDS – World Health Organisation (WHO) growth charts for Canada] and length was below −4 SDS. Head circumference was within the average range (−1 SDS), with a large anterior fontanelle. Cranial imaging and electroencephalography (EEG) were unremarkable. Initial ionized calcium level was 0.55 (1.15–1.35 mmol/l) and magnesium was 0.50 (0.65–1.05 mmol/l) with a parathyroid hormone value of 0.4 (1.6–9.30 pmol/l). After receiving boluses, values eventually stabilized and she was discharged home on replacement therapy. At 3 years of age, she was able to maintain her calcium levels off replacement, but still required magnesium supplementation. After a gastrointestinal illness, she needed to restart the supplemental calcium and this requirement has continued. Her stature is short (−5 SDS), her fontanelle remains open, but her head growth and development are within the average range. She has frontal bossing and small appearing eyes. She wears glasses and has dental caps for caries. The proband’s mother was 25 years of age at delivery. She was born as part of a dizygous twin pregnancy at term with a birth weight of 1870 g. She had her first hypocalcemic seizure at 6 days of age and was
394
subsequently found to have hypoparathyroidism. She has been on lifelong calcium supplementation, although she has not had consistent control of her levels. Her recent parathyroid hormone measurements have been in the average range. Her other medical issues include hypothyroidism, sensorineural hearing loss, and oligodontia with retention of her primary teeth. She required a modified program in school. On examination, her height is −5 SDS. She does not have a prominent forehead and her head circumference is −4 SDS. The posterior fontanelle remains open. She wears glasses. Radiographs on the proband in the newborn period were reported as unremarkable. When the proband was 3 years of age, X-rays were carried out on her mother that showed the classic findings of KCS (Fig. 1). Radiographs from the proband showed similar, but milder changes. Samples were obtained from the family and the FAM111A gene was analyzed using Sanger sequencing. The c.1706G > A (p.Arg569His) mutation that was identified in 4/5 of the KCS patients reported by Unger et al. (1) was present in the two affected individuals and not in the unaffected maternal grandparents. We report the first molecularly confirmed instance of mother-to-child transmission of KCS. Inheritance from a father to a child has not been described, despite there being an equal sex ratio of affected individuals reported in the literature (7). Hoffman et al. tried to determine the etiology of the subfertility and investigated two males with microorchidism (8). Endocrine studies of the sex hormones showed that levels were within the average range, except for elevations of the follicle-stimulating hormone. Histology of a testis revealed Leydig cell hyperplasia, but otherwise preserved anatomy. Despite these findings, a mechanism for the microorchidism was not determined. There were no comments that the penile size was outside of the average range, although in the allelic condition, osteocraniostenosis (OMIM 602361), micropenis was reported in 4/5 mutation positive males (1). Together, these data suggest that FAM111A may also be important in the development and function of male genitalia.
Letter to the Editor (a)
(c)
(b)
(d)
(e)
(f)
Fig. 1. Radiographs of the proband at 3 years and her mother at age 28 years. (a) Skull film of the proband demonstrating the large fontanelle. (b) Skull of the mother demonstrating osteosclerosis and dental anomalies. (c, d) Lower limbs of the proband showing narrow long bones with mild narrowing of the medullary cavities. (e, f) Pelvis and lower limb of the mother with greater narrowing of the medullary cavities of the tubular bones.
Acknowledgements The authors would like to thank the family for their participation and assistance. Research was supported through the FORGE Canada Consortium with funding provided by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR) and the Ontario Genomics Institute (OGI-049). K. M. B. is supported by a Clinical Investigatorship Award from the CIHR Institute of Genetics.
S.M. Nikkela,b A. Ahmedc A. Smithc J. Marcadierc D.E. Bulmanb,c K.M. Boycotta,b,c a Department of Genetics Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada b University of Ottawa, Ottawa, ON, Canada c Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada References
2. Fine DA, Rozenblatt-Rosen O, Padi M et al. Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor. PLoS Pathog 2012: 8: e1002949. 3. Kenny FM, Linarelli L. Dwarfism and cortical thickening of tubular bones: transient hypocalcemia in a mother and son. Am J Dis Child 1966: 111: 201–207. 4. Sarría A, Toledo F, Toledo J, Vega ML, Lopez S, Bueno M. Diaphysary tubular stenosis (Kenny-Caffey’s syndrome): presentation of four observations. An Esp Pediatr 1980: 13: 373–380. 5. Majewski F, Rosendahl W, Ranke M, Nolte K. The Kenny syndrome a rare type of growth deficiency with tubular stenosis, transient hypoparathyroidism and anomalies of refraction. Eur J Pediatr 1981: 136: 21–30. 6. Enriquez EJ, Toledo F, Bustamante-Cruz M, Cruz GM. Congenital medullary tubular stenosis. A case of Caffey-Kenny syndrome. Acta Orthop Scand 1988: 59: 326–327. 7. Moussaid Y, Griffiths D, Richard B et al. Oral manifestations of patients with Kenny-Caffey syndrome. Eur J Med Genet 2012: 55: 441–445. 8. Hoffman WH, Kovacs K, Li S et al. Kenny-Caffey syndrome and microorchidism. Am J Med Genet 1998: 80: 107–111.
Correspondence: Sarah M. Nikkel Department of Genetics Children’s Hospital of Eastern Ontario 401 Smyth Road, Ottawa ON, Canada Tel.: +1 613 737 7600x2611; fax: +1 613 738 4220; e-mail: [email protected]
1. Unger S, G´orna MW, Le B´echec A et al. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet 2013. Epub 14 May 2013.
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