Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita

Abstract

Pseudoachondroplasia (PSACH) and spondyloepiphyseal dysplasia congenita (SEDC) are autosomal dominant forms of short-limb short stature caused by mutations in genes that encode structural components of the cartilage extracellular matrix. PSACH results from mutations in the cartilage oligomeric matrix protein (COMP) gene, while SEDC is caused by mutations in the gene for type II procollagen (COL2A1). We report a child with a distinct skeletal dysplasia due to the combined phenotypes of PSACH and SEDC. The proband's mother had PSACH and his father had SEDC. The child was suspected of having both phenotypes on the basis of the severity of his clinical and radiographic findings, and this was confirmed by molecular analysis. The COMP gene mutation (C348R), while not previously published, is typical of those in PSACH patients, whereas the COL2A1 mutation (T1370M) is somewhat atypical, as it predicts an amino acid change within the carboxyl-terminal region of the protein. Both mutations segregated with their respective phenotypes within this family. The description and natural history of the double heterozygote phenotype may be useful in counseling families regarding risk and prognosis.

Vitreous phenotype: A key diagnostic sign in Stickler syndrome types 1 and 2 complicated by double heterozygosity

“…We describe the phenotype of two patients, one with type 1 Stickler syndrome (OMIM 108300), the second with type 2 Stickler syndrome (OMIM 604841) in combination with Albright hereditary osteodystrophy (OMIM 103580) and Treacher Collin syndrome (OMIM 154500), respectively. The cases differ from previous reports of double heterozygosity in that the genetic defects primarily affect different tissues and organs of the body [Langer et al, 1993;Unger et al, 2001;Flynn and Pauli, 2003]. The resulting phenotypes highlight the potential difficulties in diagnosis based on facial and systemic examination alone and the key role of ophthalmic and vitreous assessment to assist in the clinical diagnosis if Stickler syndrome is suspected as part of the differential diagnosis.…”

“…However, there are only a handful of published reports describing the phenotype of patients with combinations of dominantly inherited skeletal dysplasia, a result of assortative mating based on stature [Langer et al, 1993;Unger et al, 2001;Flynn and Pauli, 2003]. Although the phenomenon of assortative mating potentially applies to patients with dominantly inherited blinding disorders, there are no prior reports of double heterozygosity involving such disorders.…”

Double heterozygosity in bone growth disorders: Four new observations and review

“…The proband's respiratory complications and cervical spine instability were both considerably more severe than that of his brother and of other children with a heterozygous diagnosis for either PSACH or SEDC. Unger et al [2001] suggest that the disruption of two genes coding for interacting extracellular matrix proteins may explain the more severe phenotype in the double heterozygote. If that is a generalizable concept, then it might be possible to generate two broad groups of double heterozygosity for bone growth disorders-those coding for proteins that interact directly with each other (anticipated to result in severe manifestations) and those that do not (resulting in additive or less than additive effects).…”

The skeletal dysplasias

“…Another consideration for patients with short stature is that there is frequently nonassortative-mating, which can lead to compound phenotypes. 21 For example, homozygous achondroplasia is lethal, 22 and many newborns who inherit two different dominant mutations from parents with different disorders (compound heterozygotes) often are severely affected with combined features of both disorders. It is also important to obtain an accurate history as to the time of onset of short stature and whether it was present prenatally or not noticed until age 2 or 3 years.…”