Long‐term follow‐up of two sibs with Larsen syndrome possibly due to parental germ‐line mosaicism

Abstract

Larsen syndrome is a heterogeneous (autosomal dominant or recessive) disorder of characteristic facial changes, multiple joint dislocations, and bone deformities. Few data on the adult presentation of the recessive form of this disorder have been reported; thus, we set out to describe two sibs thought to be affected with autosomal recessive Larsen syndrome who were evaluated as infants and later as adults. Aside from secondary joint changes and the presence of cataracts, changes described in children with autosomal recessive Larsen syndrome were noted. Three years after evaluation, the sister gave birth to a daughter with Larsen syndrome. This occurrence raises the possibility of germ-line mosaicism as the mode of inheritance in this family. Thus, germ-line mosaicism must be considered in the genetic counseling of families with Larsen syndrome in which neither parent appears affected. These patients also illustrate that despite the severe skeletal and joint deformities, the prognosis can be good with careful orthopedic management.

Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): A possible locus for Fryns syndrome

“…Accordingly, sibling recurrences could be due to either low-level somatic or gonadal mosiacism in one of the parents. Other disorders previously thought to follow an autosomal recessive pattern of inheritance now known to be due to dominant mutations include campomelic dysplasia [OMIM #114290] [Lynch et al, 1993], osteogenesis imperfecta type II [OMIM #166210] [Cohn et al, 1990], and one form of Larsen syndrome [OMIM#150250] [Petrella et al, 1993]. Alternatively, our patient may have autosomal recessive Fryns syndrome, with deletion of the causal gene in the 1q41-q42.12 critical interval, combined with a mutation in the causal gene on the other chromosome 1 homolog.…”

A molecular and clinical study of Larsen syndrome caused by mutations in FLNB

“…These putative recessive entities may represent further instances of parental germline mosaicism for a heterozygotic FLNB mutation. [18][19][20] The entity described in the La Réunion Island isolate 57 58 is clearly phenotypically discrete (stature -5 SD, polydactyly, advanced skeletal maturation, radioulnar synostosis, diaphyseal bowing, metacarpophalangeal and interphalangeal dislocations, lack of accessory carpal and tarsal bones), clearly distinguishing this phenotype from autosomal dominant Larsen syndrome due to FLNB mutations. Nevertheless, on the basis of current evidence, a recessive form of Larsen syndrome cannot be ruled out.…”

“…17 Instances of sibling recurrence to unaffected parents have been retrospectively explained by parental germline mosaicism on subsequent observation of vertical transmission of the phenotype. [18][19][20] Other instances of sibling recurrence to unaffected parents may reflect the same underlying mechanism. 13 Presentations consistent with somatic mosaicism have also been reported.…”

Quantification of transmission risk in a male patient with a FLNB mosaic mutation causing Larsen syndrome: Implications for genetic counseling in postzygotic mosaicism cases

“…A few cases of apparent somatic and/or gonadal mosaicism have previously been reported in Larsen syndrome (Debeer, De Borre, De Smet, & Fryns, ; Frints, De Smet, Fabry, & Fryns, ; Petrella, Rabinowitz, Steinmann, & Hirschhorn, ). In such cases, as in other cases of disease due to somatic mosaicism, it is not usually possible to accurately determine the transmission risk to future offspring owing to a lack of quantitative information regarding the presence or absence of the mutation within the gamete pool.…”