Kenny-Caffey Syndrome, Type 2

A number sign (#) is used with this entry because of evidence that autosomal dominant Kenny-Caffey syndrome (KCS2) is caused by heterozygous mutation in the FAM111A gene (615292) on chromosome 11q12.

Gracile bone dysplasia (GCLEB; 602361) is also caused by mutation in the FAM111A gene.

Description

Kenny-Caffey syndrome is characterized by severe proportionate short stature, cortical thickening and medullary stenosis of the tubular bones, delayed closure of the anterior fontanel, eye abnormalities, and transient hypocalcemia. Patients with autosomal dominant KCS type 2 have normal intelligence (Kenny and Linarelli, 1966; Caffey, 1967; summary by Isojima et al., 2014).

See KCS1 (244460) for a discussion of an autosomal recessive form of Kenny-Caffey syndrome.

Clinical Features

Kenny and Linarelli (1966) described mother and son who were markedly dwarfed with dense tubular bones and narrow marrow cavities. Both had self-limited bouts of hypocalcemia and hyperphosphatemia documented at age 39 years in the mother and age 1 to 15 weeks in the son. Associated features were delayed closure of the fontanel, myopia and low birth weight. Mentation was normal. Radiologic features were presented in detail by Caffey (1967). The mother was 48 inches tall at age 39 years.

An isolated case was reported by Wilson et al. (1974). Boynton et al. (1979) pointed out that the severe refractive error is hyperopia, not myopia. Nanophthalmos is responsible for the hyperopia. Corneal and retinal calcification was found in an autopsy case. One patient showed pseudodoubling of the optic papilla.

McKusick (1980) observed severe hypermetropia and apparent papilledema thought to represent pseudotumor cerebri in a 6-year-old boy with Kenny-Caffey syndrome. Boynton et al. (1979) described a similar finding, with tortuous and dilated retinal vessels. They reported the only known autopsy case in a patient who died at age 19. Parathyroid tissue could not be found. Calcification was found in the basal ganglia, dentate nuclei, and parts of the cerebrum and cerebellum. The bone cortex is probably not abnormally thick; the small medulla merely leads to a radiographic impression of increased thickness.

Majewski et al. (1981) observed transmission from mother to child.

Lee et al. (1983) suggested that the hypocalcemia may be due to hypoparathyroidism: serum immunoreactive parathyroid hormone levels remained inappropriately low during spontaneous and induced hypocalcemia. The similarity in severity in males and females supports autosomal inheritance.

Larsen et al. (1985) reported the case of a 24-year-old man with short stature (about 152 cm), hypocalcemia, thin head hair, and medullated nerve fibers of both fundi and high hyperopia. Fanconi et al. (1986) found that parathyroid hormone was undetectable in 2 unrelated patients and structurally abnormal in a third. Circulating calcitonin was also undetectable. The most striking clinical features were macrocephaly, delayed closure of the anterior fontanel, and dysmorphic facies. Intelligence was normal. Two had hyperopia with papilledema. All had episodic hypocalcemia and hyperphosphatemia in the first months of life.

Enriquez et al. (1988) described a 6-year-old girl who had bilateral congenital cataracts and seizures in addition to medullary tubular stenosis. The mother and the brother had radiographic features of the bone disorder with no clinical signs or symptoms. Although both the maternal grandparents and the parents were consanguineous, inheritance in this family was probably autosomal dominant.

In an affected 18-month-old girl, Bergada et al. (1988) found growth retardation, bilateral hyperopia with poor macular development, persistently open anterior fontanel, anemia, severe hypoparathyroidism, and typical radiologic skeletal features. Analysis of restriction patterns of DNA with human parathyroid hormone probes showed no gross abnormality of the PTH gene that could contribute to the hypoparathyroidism. In addition to previously described characteristics of the syndrome, hypoplastic nails, persistent neutropenia, abnormal T-cell function, and neonatal liver disease were observed.

Franceschini et al. (1992) described 2 sibs with KCS and reviewed 24 reported cases, most of which were familial with probable autosomal dominant inheritance. The major manifestations were dwarfism, cortical thickening with medullary stenosis of the tubular bones, and delayed fontanel closure. Occasional symptomatic hypocalcemia was present in 18 of 21 cases with onset from the first few days of life to the fourth decade. Eye abnormalities were present in 17 of 24 cases, and low parathyroid hormone was found in 6 of 11.

Hoffman et al. (1998) found reports of 5 pubertal or adult-age male patients with KCS, all of whom had findings suggestive of microorchidism or infertility. They reported a 17-year-old boy with KCS who had microorchidism and elevated serum follicle-stimulating hormone levels. They also presented the testicular and pituitary histologic findings on another patient with KCS and microorchidism, who died at the age of 19 years. The first patient had normal levels of luteinizing hormone and testosterone. There was no evidence of a microdeletion of the Y chromosome. The second patient had Leydig cell hyperplasia with normal seminiferous tubules and spermatogenesis, and normal pituitary histologic findings at autopsy. The report confirmed the previous observations of microorchidism and suggested subfertility, but did not fully clarify the pathogenesis.

Molecular Genetics

In 5 patients with autosomal dominant Kenny-Caffey syndrome and 5 patients with gracile bone dysplasia (602361), Unger et al. (2013) identified heterozygosity for 6 mutations in the FAM111A gene (615292.0001-615292.0006, respectively). In the 7 families in which DNA was available from both parents, the mutations were confirmed to have arisen de novo. None of the mutations was found in the 1000 Genomes Project or NHLBI Exome Variant Server databases. The authors concluded that KCS2 and gracile bone dysplasia represent allelic disorders of differing severity.