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

Abstract

Because matings between individuals of small stature is common, information regarding double heterozygosity for dominantly inherited bone growth disorders is of considerable importance. We summarize seven occurrences of four combinations of double heterozygosity (achondroplasia/spondyloepiphyseal dysplasia congenita, achondroplasia/pseudoachondroplasia, achondroplasia/osteogenesis imperfecta type I, achondroplasia/hypochondroplasia (non-FGFR3)), and review additional reports from the literature. Each of the eight different examples of double heterozygosity for bone growth disorders now reported results in distinct phenotypic features, differing severity, and disparate expectations. We document the natural history of each. The genetic processes underlying these disorders also are examined to assess whether knowledge of molecular mechanisms can be used to predict clinical severity.

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.…”

Novel and Recurrent Mutations in the FGFR3 Gene and Double Heterozygosity Cases in a Cohort of Brazilian Patients with Skeletal Dysplasia

“…Diagnosis of double heterozygosity describes cases when the affected individual has 2 different genetic disorders, each of which could be inherited from different parents, from the same parent, or one mutation could be inherited from a parent accompanied by a simultaneous de novo mutation in another gene [Flynn and Pauli, 2003]. Information regarding double heterozygosity has practical relevance for individuals with dominantly inherited bone growth disorders due to independent recurrent risks and variable combined phenotype.…”

“…More importantly, the knowledge about the double heterozygosity phenotype is important with regards to potential severe health problems and survival of the infant. The seminal publication of Flynn and Pauli [2003] that reviewed literature data and reported 8 new observations, involving 4 double heterozygosity combinations, revealed that most frequently, ACH co-occurred with HCH, spondyloepiphyseal dysplasia congenita, pseudoachondroplasia, osteogenesis imperfecta type I/III, and Léri-Weill dyschondrosteosis. Clinical characteristics and natural history of individuals double heterozygous for the mutations leading to bone dysplasias are extremely varied and idiosyncratic to each combination [Flynn and Pauli, 2003].…”

“…The seminal publication of Flynn and Pauli [2003] that reviewed literature data and reported 8 new observations, involving 4 double heterozygosity combinations, revealed that most frequently, ACH co-occurred with HCH, spondyloepiphyseal dysplasia congenita, pseudoachondroplasia, osteogenesis imperfecta type I/III, and Léri-Weill dyschondrosteosis. Clinical characteristics and natural history of individuals double heterozygous for the mutations leading to bone dysplasias are extremely varied and idiosyncratic to each combination [Flynn and Pauli, 2003]. In their study, the authors suggested that double heterozygous mutations causing bone growth disorders may be classified into 2 broad groups: 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).…”