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 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.