Short stature and hypoparathyroidism in a child with Kenny-Caffey syndrome type 2 due to a novel mutation in FAM111A gene

Abstract

BackgroundHypoparathyroidism in children is a heterogeneous group with diverse genetic etiologies. To aid clinicians in the investigation and management of children with hypoparathyroidism, we describe the phenotype of a 6-year-old child with hypoparathyroidism and short stature diagnosed with Kenny-Caffey syndrome (KCS) Type 2 and the subsequent response to growth hormone (GH) treatment.Case presentationThe proband presented in the neonatal period with hypocalcemic seizures secondary to hypoparathyroidism. Her phenotype included small hands and feet, hypoplastic and dystrophic nails, hypoplastic mid-face and macrocrania. Postnatal growth was delayed but neurodevelopment was normal. A skeletal survey at 2 years of age was suggestive of KCS Type 2 and genetic testing revealed a novel de novo heterozygous mutation c.1622C > A (p.Ser541Tyr) in FAM111A. At 3 years and 2 months, her height was 80cms (SDS −3.86). She had normal overnight GH levels. GH therapy was commenced at a dose of 4.9 mg/m2/week for her short stature and low height velocity of 5cms/year. At the end of the first and second years of GH treatment, height velocity was 6.5cms/year and 7.2cms/year, respectively with maximal dose of 7.24 mg/m2/week.ConclusionThis case highlights the phenotype and the limited response to GH in a child with genetically proven KCS type 2. Long-term registries monitoring growth outcomes following GH therapy in patients with rare genetic conditions may help guide clinical decisions regarding the use and doses of GH in these conditions.

FAM111A protects replication forks from protein obstacles via its trypsin-like domain

“…These results raised the possibility that FAM111A might have autocleavage activity in vivo. Interestingly, germline mutations have been found in FAM111A in patients with Kenny-Caffey syndrome (KCS) and osteocraniostenosis (OCS) [38][39][40][41] , and it has been postulated that these mutations may cause gain-of-function FAM111A activity because the mutations are always heterozygous and no loss-of-function mutations (i.e., deletions and truncations) have been reported 38 . We therefore tested whether the mutations found in KCS and OCS patients produce constitutively active FAM111A.…”

Ophthalmologic Impairment and Intellectual Disability in a Girl Presenting Kenny-Caffey Syndrome Type 2

“…3,7 In silico analyses also showed that this de novo variant would not significantly affect protein function. 7,14 We performed a three-dimensional protein model to obtain an insight on the consequences of the altered amino acid within protein structure. As shown in ►Fig.…”

“…9 Growth hormone (GH) treatment seems to play a limited role in the management of these patients, even with KCS2. 8,9,14,16 However, a study performed an evaluation of the use of GH in five patients with KCS and four of them showed a normal response. 17 Moreover, another study reported a patient who underwent treatment with GH therapy (0.5 IU/kg/wk) at 7 years and 5 months of age.…”

“…KCS1, in addition to being transmitted by an autosomal recessive pattern of inheritance, differs from autosomal dominant KCS2 due to delays in mental development and microcephaly. 3,4,6,14 KCS2 patients present a normal intelligence, besides the occurrence, for example, of seizures and cortical calcifications. 3,4 In our case, the presence of neuropsychomotor and speech delay, as well as learning disability is remarkable.…”

Overlapping phenotype comprising Kenny‐Caffey type 2 and Sanjad‐Sakati syndromes: The first case report

“…Morphological examination showed prominent forehead, narrow nasal base with pinched nasal tip, apparent small eyes, and broad cheeks (Table S1), leading to treatment discontinuation for 8 months, until a new hypoparathyroidism episode (Table S1) (p.Arg569His) in FAM111A gene. This variant was classified as pathogenic based on its previous description in patients with KCS2 (Abraham et al, 2017;Guo et al, 2014;Isojima et al, 2014;Nikkel et al, 2014;Unger et al, 2013), and the absence in 60,000 control individuals on Exome Aggregation Consortium (ExAC).…”