Lacrimo-Auriculo-Dento-Digital (LADD) Syndrome

A father presented to a pediatrics clinic with his daughter for a well-child visit. The father had shortened forearms and 3 fingers on each hand, along with small, gray, peg-shaped lower incisors and capped upper incisors (Figures 1-3). He also stated that he had never been able to produce tears, and because of recurrent episodes of conjunctivitis as a child, he had required surgery for lacrimal duct stenosis. Additionally, he reported a solitary kidney and an absence of ulnar bones. He had no hearing problems or difficulty eating or swallowing. His mother had been the only other affected family member.

Discussion. Longitudinal dysplasias of the upper extremities include radial and ulnar deficiencies. Ulnar involvement is 10 times less common, and only 1 in 4 cases is bilateral. Most cases are sporadic, but some occur as part of a recognized syndrome (Table). Clinically, because the father had abnormal development in at least 2 ectodermal structures, he received a diagnosis of lacrimo-auriculo-dento-digital (LADD) syndrome, also known as Levy-Hollister syndrome.

LADD syndrome was first described by Hollister and colleagues in 1973,¹ and since then more than 60 cases have been reported. It is an autosomal dominant form of ectodermal dysplasia (a heterogeneous group of disorders related to abnormal development of 2 or more ectodermal structures) characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb-segment anomalies. Solitary kidneys, renal agenesis leading to neonatal death, and malformations of the lungs and genitalia also have been described.^1,2 Upper extremity abnormalities occur in 95% of patients with LADD syndrome; lower extremity involvement is less frequent. The severity of limb involvement ranges from clinodactyly to the absence of radial bones.²

Mutations on the fibroblast growth factor receptor (FGFR) genes FGFR2, FGFR3, or FGF10 are associated with LADD syndrome. The FGFR genes stimulate cells to form the structures that make up the lacrimal glands, salivary glands, ears, skeleton, and other organs.³

Medical management includes continued ophthalmologic evaluation to avoid corneal scarring from chronic dacryocystitis; hearing tests to detect sensorineural, conductive, or mixed-type hearing loss; and surveillance of renal function when a solitary kidney is present. Surgical intervention may be needed to improve arm and hand function, lacrimal abnormalities, and hearing impairments.

Outcome of the case. When patients or their parents present with a constellation of physical anomalies, genetic causes must be considered. Syndrome identification is important not only for educational purposes but also for future reproductive decision making. Identification can be difficult due to the wide range of phenotypic presentations possible.

Upon questioning the father, we found that he had adopted our patient, and that he had been advised of the risk in any future biological children.

References:

1. Hollister DW, Klein SH, De Jager HJ, Lachman RS, Rimoin DL. The lacrimo-auriculo-dento-digital syndrome. J Pediatr. 1973;83(3):438-444.
2. Kreutz JM, Hoyme E. Levy-Hollister syndrome. Pediatrics. 1988;82(1):96-99.
3. Rohmann E, Brunner HG, Kayserili H, et al. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38(4):414-417.
4. Rinne T, Hamel B, van Bokhoven H, Brunner HG. Pattern of p63 mutations and their phenotypes—update. Am J Med Genet A. 2006;140(13):1396-1406.
5. Basson CT, Solomon SD, Weissman B, et al. Genetic heterogeneity of heart-hand syndromes. Circulation. 1995;91(5):1326-1329.
6. Farahmandi MV, Nadjafi J. Familial ulnar club hand: case report in 3 successive generations. Iran J Radiol. 2004;2(1-2):17-19.
7. Schinzel A. Ulnar-mammary syndrome. J Med Genet. 1987;24(12):778-781.