Further delineation of phenotype and genotype of Kenny-Caffey syndrome type 2 (phenotype and genotype of KCS type 2).

BACKGROUND: Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention. METHODS: We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases. RESULTS: There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases. CONCLUSION: We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father-to-daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.

Clinical and genetic features of Kenny-Caffey syndrome type 2 with multiple electrolyte disturbances: A case report.

BACKGROUND: Hypoparathyroidism, which can be sporadic or a component of an inherited syndrome, is the most common cause of hypocalcemia. If hypocalcemia is accompanied by other electrolyte disturbances, such as hypokalemia and hypomagnesemia, then the cause, such as renal tubular disease, should be carefully identified. CASE SUMMARY: An 18-year-old female visited our clinic because of short stature and facial deformities, including typical phenotypes, such as low ear position, depression of the nasal bridge, small hands and feet, and loss of dentition. The lab results suggested normal parathyroid hormone but hypocalcemia. In addition, multiple electrolyte disturbances were found, including hypokalemia, hypocalcemia and hypomagnesemia. The physical signs showed a short fourth metatarsal bone of both feet. The X-ray images showed cortical thickening of long bones and narrowing of the medulla of the lumen. Cranial computed tomography indicated calcification in the bilateral basal ganglia. Finally, the genetic investigation showed a de novo heterogenous mutation of "FAM111A" (c. G1706A:p.R569H). Through a review of previously reported cases, the mutation was found to be the most common mutation site in Kenny-Caffey syndrome type 2 (KCS2) cases reported thus far (16/23, 69.6%). The mutation was slightly more prevalent in females than in males (11/16, 68.8%). Except for hypocalcemia, other clinical manifestations are heterogeneous. CONCLUSION: As a rare autosomal dominant genetic disease of hypoparathyroidism, the clinical manifestations of KCS2 are atypical and diverse. This girl presented with short stature, facial deformities and skeletal deformities. The laboratory results revealed hypocalcemia as the main electrolyte disturbance. Even though her family members showed normal phenotypes, gene detection was performed to find the mutation of the FAM111A gene and confirmed the diagnosis of KCS2.

Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features.

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.

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

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.

Functions and evolution of FAM111 serine proteases.

Proteolysis plays fundamental and regulatory roles in diverse cellular processes. The serine protease FAM111A (FAM111 trypsin-like peptidase A) emerged recently as a protease involved in two seemingly distinct processes: DNA replication and antiviral defense. FAM111A localizes to nascent DNA and plays a role at the DNA replication fork. At the fork, FAM111A is hypothesized to promote DNA replication at DNA-protein crosslinks (DPCs) and protein obstacles. On the other hand, FAM111A has also been identified as a host restriction factor for mutants of SV40 and orthopoxviruses. FAM111A also has a paralog, FAM111B, a serine protease with unknown cellular functions. Furthermore, heterozygous missense mutations in FAM111A and FAM111B cause distinct genetic disorders. In this review, we discuss possible models that could explain how FAM111A can function as a protease in both DNA replication and antiviral defense. We also review the consequences of FAM111A and FAM111B mutations and explore possible mechanisms underlying the diseases. Additionally, we propose a possible explanation for what drove the evolution of FAM111 proteins and discuss why some species have two FAM111 proteases. Altogether, studies of FAM111 proteases in DNA repair, antiviral defense, and genetic diseases will help us elucidate their functions and the regulatory mechanisms.

Oral rehabilitation of a patient with Kenny-Caffey syndrome using telescopic overdenture.

Kenny-Caffey syndrome (KCS) is a rarely reported autosomal disorder characterized by skeletal, ocular, and oral manifestations. Oral features such as microdontia, hypodontia, malalignment of teeth, bone loss, and difficulty in mastication results in serious esthetic and functional handicap. The prosthetic rehabilitation of such patients is challenging, especially when implant placement is not a good choice due to poor Vitamin D levels. The existing literature is scarce in describing the treatment options. This case report describes the oral rehabilitation of a patient affected with KCS using telescopic overdenture.

Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull.

Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.

FAM111A induces nuclear dysfunction in disease and viral restriction.

Mutations in the nuclear trypsin-like serine protease FAM111A cause Kenny-Caffey syndrome (KCS2) with hypoparathyroidism and skeletal dysplasia or perinatally lethal osteocraniostenosis (OCS). In addition, FAM111A was identified as a restriction factor for certain host range mutants of the SV40 polyomavirus and VACV orthopoxvirus. However, because FAM111A function is poorly characterized, its roles in restricting viral replication and the etiology of KCS2 and OCS remain undefined. We find that FAM111A KCS2 and OCS patient mutants are hyperactive and cytotoxic, inducing apoptosis-like phenotypes such as disruption of nuclear structure and pore distribution, in a protease-dependent manner. Moreover, wild-type FAM111A activity causes similar nuclear phenotypes, including the loss of nuclear barrier function, when SV40 host range mutants attempt to replicate in restrictive cells. Interestingly, pan-caspase inhibitors do not block these FAM111A-induced phenotypes, implying it acts independently or upstream of caspases. In this regard, we identify nucleoporins and the associated GANP transcription/replication factor as FAM111A interactors and candidate targets. Overall, we reveal a potentially unifying mechanism through which deregulated FAM111A activity restricts viral replication and causes KCS2 and OCS.

Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.

Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.

Genotype-phenotype spectrum in isolated and syndromic nanophthalmos.

PURPOSE: To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their functional characterization and (ii) to study the association of retinal dystrophy in patients with MFRP variants, based on a detailed literature review of genotype-phenotype correlations. METHODS: Patients with nanophthalmos and available family members received a comprehensive ophthalmological examination. Genetic analysis was based on whole-exome sequencing and variant calling in core genes including MFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRF and FAM111A. A minigene assay was performed for functional characterization of a splice site variant. RESULTS: Seven patients, aged between three and 65 years, from five unrelated families were included. Novel pathogenic variants in MFRP (c.497C>T, c.899-3C>A, c.1180G>A), and PRSS56 (c.1202C>A), and a recurrent de novo variant in FAM111A (c.1706G>A) in a patient with Kenny-Caffey syndrome type 2, were identified. In addition, we report co-inheritance of MFRP-related nanophthalmos and ADAR-related Aicardi-Goutières syndrome. CONCLUSION: Nanophthalmos is a genetically heterogeneous condition, and the severity of ocular manifestations appears not to correlate with variants in a specific gene. However, retinal dystrophy is only observed in patients harbouring pathogenic MFRP variants. Furthermore, heterozygous carriers of MFRP and PRSS56 should be screened for the presence of high hyperopia. Identifying nanophthalmos as an isolated condition or as part of a syndrome has implications for counselling and can accelerate the interdisciplinary care of patients.

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

Kenny-Caffey syndrome (KCS) is a rare hereditary skeletal disorder involving hypoparathyroidism. The autosomal dominant form (KCS2), caused by heterozygous pathogenic variants in the FAM111A gene, is distinguished from the autosomal recessive form (KCS1) and Sanjad-Sakati syndrome (SSS), both caused by pathogenic variants in the tubulin folding cofactor E (TBCE) gene, by the absence of microcephaly and intellectual disability. We present a patient with KCS2 caused by a de novo pathogenic variant c.1706G>A (p.Arg569His) in FAM111A gene, presenting intellectual disability and microcephaly, which are considered to be typical signs of SSS. We suggest that KCS1, KCS2, and SSS may not represent mutually exclusive clinical entities, but possibly an overlapping spectrum.

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

Kenny-Caffey syndrome (KCS) is a rare genetic condition characterized by growth retardation, bone abnormalities, and hypoparathyroidism. Herein, we report an unusual case of a 10-year-old girl with Kenny-Caffey syndrome type 2 (KCS2) presenting with vision impairment-suspected maculopathy and intellectual disability. Endocrine evaluation showed low calcium and high phosphorus plasma levels. Radiographic evaluation revealed short metacarpal bones and delayed bone age. Sequencing analysis showed a missense variant in FAM111A (R569H), unidentified in her parents. Better understanding of potential neurological and ophthalmological findings in KCS2 patients is important to improve quality of life of these patients as usually they exhibit long survival.

Síndrome Kenny-Caffey en varios miembros de una familia / Kenny-Caffey Syndrome in several members of a family

El síndrome Kenny-Caffey es una enfermedad hereditaria, extremadamente rara, que se transmite de forma autosómica dominante y se caracteriza por retraso del crecimiento, anomalías oculares, hipocalcemia y engrosamiento cortinal de los huesos largos, cuyo diagnóstico precoz e intervención temprana ayudarán a mejorar la calidad de vida de los afectados. Se presenta a 2 miembros de una familia (la madre y un hijo), atendidos en la consulta de genética clínica de la provincia de Holguín, con características clínicas que se correspondían con dicho síndrome, para compartir estos hallazgos con la comunidad médica en general, pues llamó la atención que estuvieran afectados 3 personas de una misma familia, aunque solo se describe a 2 de ellos

The Kenny-Caffey syndrome is a hereditary, extremely strange disease that is transmitted in an autosomal dominant way and is characterized by growth failure, ocular anomalies, hypocalcemia and cortinal swelling of the long bones whose early diagnosis and intervention will help to improve the life quality of affected patients. Two members of a family are presented (mother and a son), assisted in the clinical genetics service in Holguín, with clinical characteristics that fitted with this syndrome, to share these findings with the medical community in general, because the fact that 3 people of the same family were affected attracted attention, although just 2 of them are described

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

BACKGROUND: Hypoparathyroidism 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 PRESENTATION: The 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. CONCLUSION: This 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.

Kenny Caffey syndrome with severe respiratory and gastrointestinal involvement: expanding the clinical phenotype.

Kenny Caffey syndrome (KCS) is a rare syndrome reported almost exclusively in Middle Eastern populations. It is characterized by severe growth retardation-short stature, dysmorphic features, episodic hypocalcaemia, hypoparathyroidism, seizures, and medullary stenosis of long bones with thickened cortices. We report a 10-year-old boy with KCS with an unusually severe respiratory and gastrointestinal system involvement-features not previously described in the literature. He had severe psychomotor retardation and regressed developmentally from walking unaided to sitting with support. MRI brain showed bilateral hippocampal sclerosis, marked supra-tentorial volume loss and numerous calcifications. A 12 bp deletion of exon 2 of tubulin-specific chaperone E (TBCE) gene was identified and the diagnosis of KCS was confirmed. Hypercarbia following a sleep study warranted nocturnal continuous positive airway pressure (CPAP) when aged 6. When boy aged 8, persistent hypercarbia with increasing oxygen requirement and increased frequency and severity of lower respiratory tract infections led to progressive respiratory failure. He became fully dependent on non-invasive ventilation and by 9 years he had a tracheotomy and was established on long-term ventilation. He developed retching, vomiting and diarrhea. Chest CT showed changes consistent with chronic aspiration, but no interstitial pulmonary fibrosis. He died aged 10 from respiratory complications.

A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2.

Kenny-Caffey syndrome (KCS) is a rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form of KCS (KCS type 2 [KCS2]) is distinguished from the autosomal recessive form of KCS (KCS type 1 [KCS1]), which is caused by mutations of the tubulin-folding cofactor E (TBCE) gene, by the absence of mental retardation. In this study, we recruited four unrelated Japanese patients with typical sporadic KCS2, and performed exome sequencing in three patients and their parents to elucidate the molecular basis of KCS2. The possible candidate genes were explored by a de novo mutation detection method. A single gene, FAM111A (NM_001142519.1), was shared among three families. An identical missense mutation, R569H, was heterozygously detected in all three patients but not in the unaffected family members. This mutation was also found in an additional unrelated patient. These findings are in accordance with those of a recent independent report by a Swiss group that KCS2 is caused by a de novo mutation of FAM111A, and R569H is a hot spot mutation for KCS2. Although the function of FAM111A is not known, this study would provide evidence that FAM111A is a key molecule for normal bone development, height gain, and parathyroid hormone development and/or regulation.

Kenny-Caffey syndrome type 1 in an Egyptian girl.

Kenny-Caffey syndrome type 1 (KCS1) (OMIM 244460) is a rare syndrome characterized by growth retardation, uniformly small slender long bones with medullary stenosis, thickened cortex of the long bones, hypocalcemia possibly with tetany at an early age and normal intelligence. The primary outcome of KCS1 is short stature. We present here an Egyptian girl aged 32 months with typical feature of KCS1.