For questions and more detailed information please contact Bernd Wollnik ().
Most of the patients with an identified mutation in FGF10, FGFR2, or FGFR3 genes do show an affection of the lacrimal/salivary system and digital anomalies, mainly affecting the thumbs. Syndactylies are infrequently associated. Cup-shaped ears are present in approximately 60% and hearing loss (sensorineural and mixed type) in about 50% of patients. Due to the dysfunction of the salivary glands in many affected individuals, these patients develop xerostomia (dry mouth) and early onset caries. Dental anomalies such as microdontia and hypodontia are frequently observed. Facial dysmorphism can be present in patients, but are not typical. A mild expression of the disease affecting only the lacrimal and salivary system has been reported (aplasia of lacrimal and salivary glands, ALSG, MIM #180920).
Typical anomalies in LADD syndrome:
Diagnosis is based on the clinical findings. Due to variable clinical expression of the disease even within a single family, clinical diagnosis could be difficult if less than two of the four main systems (lacrimal, aural, dental, digital) are affected. Molecular genetic testing helps to verify the clinical diagnosis.
Dominant mutations in FGF10, FGFR2, or FGFR3 cause LADD syndrome in approximately 70% of clinically diagnosed patients with LADD syndrome. While mutations in FGF10 and FGFR2 are equally frequent, only one family with a mutation in FGFR3 has yet been reported. The FGF10 mutation spectrum includes missense and nonsense mutations as well as large deletions and duplications of FGF10. For this reason, MLPA analysis is done for diagnostic testing in addition to the sequencing of the 3 coding exons of FGF10. All mutations identified in FGFR2 and FGFR3 are confined to the tyrosine kinase (TK) domain of the receptors. Therefore, molecular testing includes only the TK domain of the receptors. No hot-spot mutationis described. A single patient carrying a homozygous FGFR2 mutation inherited from healthy carrier parents is known (B. Wollnik, personal communication). If this case represents an autosomal recessive inheritance or double dominant mutation with reduced penetrance in the parents is not clear.
Functional analysis of LADD mutations showed that FGF10 mutations cause haploinsufficiency, while the TK-domain mutations in FGFR2 and FGFR3 lead to a reduced receptor activity via a dominant-negative effect.
Genotype phenotype correlation:
There is no obvious genotype phenotype correlation. Inter- and intrafamilial variability is present and not related with a specific gene or specific type of mutation.
Typical LADD syndrome is inherited in an autosomal dominant manner. This means, that children of an affected person have a 50% risk to carrier the mutation and to present clinical features of LADD syndrome. The severity of the clinical findings based on the clinical findings present in the mother/father or based on the kind of mutation identified in the family can not be predicted. If additionally an autosomal recessive form of inheritance exists is unclear and currently under investigation.
Within the CRANIRARE consortium, the partner in Cologne (contact: B. Wollnik) works on the clinical, genetic and functional aspects of LADD syndrome. There is evidence for additional causative genes and the group in Cologne aims to identify these. Given the large phenotypic variability in patients with LADD syndrome, also genetic modifiers of the clinical expression of the disease will be determined and further functional analysis of identified mutations will give novel insights into the pathophysiology of the disease. We are still collecting patients, this means clinical data and DNA or blood samples, for taking part in this project. Detailed information and consent forms can be downloaded from our website: www.cranirare.eu.
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