Short Stature And Advanced Bone Age, With Or Without Early-Onset Osteoarthritis And/or Osteochondritis Dissecans

A number sign (#) is used with this entry because of evidence that short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) is caused by heterozygous mutation in the ACAN gene (155760) on chromosome 15q26.

Description

Patients with SSOAD exhibit a broad phenotypic spectrum involving short stature associated with advanced bone maturation and early-onset osteoarthritis (OA), as well as mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disc disease and osteochondritis dissecans, which is characterized by separation of articular cartilage and subchondral bone from the articular surface. Phenotypes are highly variable even among patients within the same family, and there are no apparent genotype-phenotype correlations (Dateki et al., 2017).

The term 'dissecans' comes from 'dis' meaning 'from' and 'secare' meaning 'cut off,' and is not to be confused with 'desiccans' derived from 'desiccare' meaning to 'dry up.' Dissecans refers to the appearance of part of the bone having been cut away.

Clinical Features

Zellweger and Ebnother (1951) reported a family in which the 4 members with osteochondritis dissecans were dwarfed. In the family reported by Pick (1955), the affected mother and 3 affected daughters were short. Gardiner (1955) reported OD of the knees in a sister and 2 brothers.

Tobin (1957) described father and 2 sons with the combination of OD and tibia vara (188700); a daughter had only OD.

Stougaard (1961) observed OD of the knees and/or elbows in 9 persons in 3 generations of a family from Denmark. A pair of twins thought to be identical were affected.

Andrew et al. (1981) described a family in which 12 persons in 4 generations had OD of knees or elbows or both. Affected persons were short (female adult height, 132-149 cm). Phillips and Grubb (1985) also observed multiple osteochondritis dissecans in association with short stature (adult males, 62-63 inches; adult females, 59 inches) in 4 successive generations with male-to-male transmission.

Stattin et al. (2008) studied a 5-generation family from northern Sweden with 15 living affected members with autosomal dominant OD. This family had previously been reported by Stougaard (1964). The main clinical findings were disproportionate short stature with long trunk in relation to the body height, early-onset OA, and OD in knees and/or elbows. In 12 of the 15 patients, onset was during late childhood or adolescence and 7 of the 12 had developed OA. Four of 5 affected individuals with OD in the elbow had experienced ulnar nerve entrapment and had undergone ulnar nerve transposition. Stattin et al. (2008) showed that the short stature among affected subjects is a result of the reduced pubertal growth and suggested that children with familial OD might benefit from growth hormone treatment. Stattin et al. (2008) suggested that OA is a frequent complication in familial OD even though the lesions appear before epiphyseal closure.

Nilsson et al. (2014) reported 3 unrelated families in which affected individuals presented with short stature and a history of early growth cessation or childhood short stature, with advancement of bone age and normal endocrine evaluations. Patients in families 1 and 2 showed mild facial dysmorphism, chiefly mild midface hypoplasia and flat nasal bridge. Other features included brachydactyly in families 1 and 2, broad great toes in family 2, and short thumbs in family 3; also in family 3, 1 patient had early-onset OA and another exhibited OD. None of the patients showed signs of skeletal dysplasia.

Quintos et al. (2015) studied a 5.5-year-old Asian/African American boy who had proportionate short stature and significantly advanced bone age, as well as midface hypoplasia and flat nasal bridge. Skeletal survey showed no evidence of skeletal dysplasia, and hormonal evaluation was normal. His mother showed mild short stature (-2.6 SDS), whereas his maternal grandfather showed severe short stature (-4.7 SDS). Both adults denied any history of arthritis, but the mother had had 'bone chips' in her knee removed by arthroscopy and had sacroiliac joint inflammation.

Gkourogianni et al. (2017) described an international cohort of 103 affected individuals from 20 families with short stature and heterozygous mutations in the ACAN gene (see MOLECULAR GENETICS), including the families originally reported by Stougaard (1964), Nilsson et al. (2014), and Quintos et al. (2015). Affected children were born with low-normal birth lengths; short stature became more pronounced and was mostly proportionate in childhood. Bone age was markedly advanced in 6 families, whereas the remaining 14 families showed only modestly advanced or normal bone age; none showed delayed bone age. Children had early growth cessation and/or decreased pubertal growth spurts, and short stature was obvious and often showed some disproportion in adulthood. Dysmorphic features were variable, with affected individuals in 8 of the 20 families showing mild midface hypoplasia and flat nasal bridge, and frontal bossing in 2 families. Brachydactyly was reported in 5 families, and in 4 of those families, affected individuals also had notably short thumbs. Complete skeletal surveys, performed on 8 patients, showed no or subtle signs of skeletal dysplasia. Early-onset OA was present in 12 families, most commonly affecting the knees, with severe OA by the second to fourth decades of life; penetrance appeared to be complete but with a variable degree of severity among the families. In 3 of these families, including the Swedish family originally reported by Stougaard (1964), the OA was associated with OD. In addition, back pain was a common complaint in affected adults from 11 families, and 14 adults and 3 children had confirmed disc disease or symptoms consistent with intervertebral disc disease. Fourteen children and 5 adults had received growth hormone (GH; 139250) treatment, with a modest response. Treatment with gonadotropin-releasing hormone (GnRH; see 152760) analogs was administered in 5 patients, and appeared to halt bone age progression.

Van der Steen et al. (2017) described affected members of 3 Dutch families with short stature, advanced bone age, early-onset OA, and a mutation in the ACAN gene (see MOLECULAR GENETICS). Dysmorphic features, which varied even within families, included midface hypoplasia, short thumbs, exaggerated lumbar lordosis, and broad great toes. In 1 family (family B) the 14-year-old male proband exhibited OD in both knees. The authors noted that their findings suggested that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRH analog.

Dateki et al. (2017) reported a Japanese family in which 2 brothers had short stature and advanced bone age. Combined GH and GnRH therapy appeared to slow bone age acceleration and accelerate height growth in the older brother, whereas the younger brother, who received only GnRH, failed to show marked effects in height growth and still showed advanced bone age after 3 years of therapy. The older brother had no dysmorphic features, but the younger brother exhibited mild midface hypoplasia, mild lordosis, and brachydactyly. Their mother and maternal aunt also had short stature and mild midface hypoplasia; in addition, the mother had severe lower back pain and had been diagnosed with multiple lumbar disc herniations (L1/2 through L5/S1) at 10 years of age, although she had no symptoms in other joints.

Inheritance

The inheritance pattern of OD in the large Swedish family reported by Stougaard (1964) and Stattin et al. (2008) was autosomal dominant.

Population Genetics

Linden (1976) estimated the prevalence of OD in the knee in Sweden to be 15 to 29 per 100,000, with a 2:1 preponderance in men.

Mapping

Stattin et al. (2010) performed a genomewide linkage analysis in the family originally described by Stougaard (1964) with autosomal dominant familial osteochondritis dissecans. In total, the study comprised 53 family members, including 19 affected individuals. A peak lod score was obtained at marker D15S127 on chromosome 15q26. Refined mapping revealed that all affected individuals shared a 10.5-Mb haplotype restricted by the polymorphic markers D15S205 and D15S130. They identified the gene encoding aggrecan (ACAN) as a prime candidate for the disorder.

Molecular Genetics

Stattin et al. (2010) performed sequence analysis of the complete coding region of the ACAN gene in the Swedish family segregating autosomal dominant OD originally reported by Stougaard (1964). They identified a heterozygous missense mutation (V2303M; 155760.0003) in all 19 affected members. The mutation was not found in any unaffected family member or in 230 control chromosomes derived from unrelated healthy Swedes. The mutation occurred in the C-type lectin domain of the aggrecan G3 domain, which mediates interactions with other proteins in the cartilage extracellular matrix (ECM). Stattin et al. (2010) suggested that loss of G3 interactions in the mutant protein might contribute to a disorganized ECM in the growth plate and thus lead to decreased long bone growth in the affected individuals.

In 3 families with short stature, advanced bone age, and premature growth cessation, with variable early-onset osteoarthritis and osteochondritis dissecans, Nilsson et al. (2014) performed whole-exome sequencing and identified heterozygous mutations in the ACAN gene (155760.0004-155760.0006) that segregated fully with disease in each family.

In a 5.5-year-old Asian/African American boy, his mother, and his maternal grandfather who had short stature, advanced bone age, and premature growth cessation, Quintos et al. (2015) sequenced the candidate gene ACAN and identified heterozygosity for a 1-bp deletion (155760.0007). The mutation was not found in the unaffected father or brother, or in public variant databases.

Gkourogianni et al. (2017) studied an international cohort of 103 patients from 20 families, including the families originally reported by Stougaard (1964), Nilsson et al. (2014), and Quintos et al. (2015), who exhibited short stature and premature growth cessation, with or without variable early-onset osteoarthritis and osteochondritis dissecans, and in whom heterozygous mutations in the ACAN gene (see, e.g., 155760.0003-155760.0011) had been identified. Variation in adult height was not larger than that of the general population, suggesting that different mutations had a similar effect on final height, and there was no obvious genotype/phenotype correlation for early-onset osteoarthritis, suggesting that additional genetic and environmental factors might modify susceptibility to osteoarthritis.

In a cohort of 29 Dutch children from 26 families with short stature and advanced bone age, van der Steen et al. (2017) sequenced the ACAN gene and identified 3 families in which affected members carried heterozygous mutations, including 1 family (family B) in which the proband exhibited osteochondritis dissecans (see 155760.0012). ACAN mutations were associated with additional characteristics, including midface hypoplasia (p = 0.003), joint problems (p = 0.010), and broad great toes (p = 0.003). The authors concluded that ACAN sequencing should be considered in children who are born small for gestational age and exhibit persistent short stature, advanced bone age, and midface hypoplasia, joint problems, or broad great toes.

In a Japanese family with short stature, advanced bone age, and mild midface hypoplasia, as well as brachydactyly in 1 patient and early-onset lumbar disc herniation in another, Dateki et al. (2017) performed whole-exome sequencing and identified heterozygosity for a 1-bp deletion in the ACAN gene (155760.0013).

History

Hanley et al. (1967) observed OD in the femur at the knee and in the capitellum of the humerus in 2 brothers who also showed hypertelorism, finger contractures, peculiarly shaped ears, sternal deformity, and cryptorchidism. Both parents seemed normal. Escobar and Weaver (1978) suggested that these brothers had Aarskog syndrome (305400), and Berry et al. (1980) stated that they 'undoubtedly had Aarskog's syndrome.' Reexamination of the clinical photographs showed that at least one of the brothers clearly had a 'saddle-bag scrotum' typical of that condition.