A rare cause of short stature: Kenny-Caffey syndrome type 2 – a case report and literature review

Kaleta, Dagmara; Zapolnik, Paweł; Mazur, Artur; Pyrkosz, Antoni

doi:10.5114/polp.2020.103491

Cited by 4 publications

(1 citation statement)

References 11 publications

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“…The search keywords included "Kenny−Caffey syndrome type 2" or "FAM111A". The available data on clinical evaluations and genetic findings were extracted and summarized (Table 1) (10,11,16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

Section: Literature Reviewmentioning

confidence: 99%

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Ohmachi

Urai²,

Bando³

et al. 2023

Front. Endocrinol.

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Kenny–Caffey syndrome type 2 (KCS2) is an extremely rare skeletal disorder involving hypoparathyroidism and short stature. It has an autosomal dominant pattern of inheritance and is caused by variants in the FAM111 trypsin-like peptidase A (FAM111A) gene. This disease is often difficult to diagnose due to a wide range of more common diseases manifesting hypoparathyroidism and short stature. Herein, we present the case of a 56-year-old female patient with idiopathic hypoparathyroidism and a short stature. The patient was treated for these conditions during childhood. Upon re-evaluating the etiology of KCS2, we suspected that the patient had the disorder because of clinical manifestations, such as cortical thickening and medullary stenosis of the bones, and lack of intellectual abnormalities. Genetic testing identified a heterozygous missense variant in the FAM111A gene (p.R569H). Interestingly, the patient also had bilateral sensorineural hearing loss and vestibular dysfunction, which have been rarely described in previous reports of pediatric cases. In KCS2, inner ear dysfunction due to Eustachian tube dysfunction may progress in middle age or later. However, this disease is now being reported in younger patients. Nevertheless, our case may be instructive of how such cases emerge chronically after middle age. Herein, we also provide a literature review of KCS2.

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Section: Literature Reviewmentioning

confidence: 99%

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Ohmachi

Urai²,

Bando³

et al. 2023

Front. Endocrinol.

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Homozygous synonymous FAM111A variant underlies an autosomal recessive form of Kenny-Caffey syndrome

Bonde,

Abdelrazek,

Seif

et al. 2024

J Hum Genet

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FAM111A (family with sequence similarity 111 member A) is a serine protease and removes covalent DNA-protein cross-links during DNA replication. Heterozygous gain-of-function variants in FAM111A cause skeletal dysplasias, such as the perinatal lethal osteocraniostenosis and the milder Kenny-Caffey syndrome (KCS). We report two siblings born to consanguineous parents with dysmorphic craniofacial features, postnatal growth retardation, ophthalmologic manifestations, hair and nail anomalies, and skeletal abnormalities such as thickened cortex and stenosis of the medullary cavity of the long bones suggestive of KCS. Using exome sequencing, a homozygous synonymous FAM111A variant, NM_001312909.2:c.81 G > A; p.Pro27=, that affects the last base of the exon and is predicted to alter FAM111A pre-mRNA splicing, was identified in both siblings. We identified aberrantly spliced FAM111A transcripts, reduced FAM111A mRNA levels, and near-complete absence of FAM111A protein in fibroblasts of both patients. After treatment of patient and control fibroblasts with different concentrations of camptothecin that induces covalent DNA-protein cross-links, we observed a tendency towards a reduced proportion of metabolically active cells in patient compared to control fibroblasts. However, under these culture conditions, we did not find consistent and statistically significant differences in cell cycle progression and apoptotic cell death between patient and control cells. Our findings show that FAM111A deficiency underlies an autosomal recessive form of FAM111A-related KCS. Based on our results and published data, we hypothesize that loss of FAM111A and FAM111A protease hyperactivity, as observed for gain-of-function patient-variant proteins, may converge on a similar pathomechanism underlying skeletal dysplasias.

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Expanding the Phenotypic Spectrum of Kenny–Caffey Syndrome

Schigt

Bald

Eerden

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish. Objective The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate on complications that may arise in these disorders. Design We clinically and genetically analyzed ten KCS2 patients from seven families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by three researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by two independent researchers. Results Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low PTH levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23) and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common. Conclusions Our case series established chronic kidney disease as a new feature of KCS2. In literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

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A rare cause of short stature: Kenny-Caffey syndrome type 2 – a case report and literature review

Cited by 4 publications

References 11 publications

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Homozygous synonymous FAM111A variant underlies an autosomal recessive form of Kenny-Caffey syndrome

Expanding the Phenotypic Spectrum of Kenny–Caffey Syndrome

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