Dyggve-Melchior-Clausen syndrome is a very rare genetic disorder that is characterized by a childhood-onset of mental retardation, microcephaly, various facial changes, and a range of skeletal abnormalities that affect the trunk, the spine, and the limbs. An autosomal recessive pattern of inheritance is established and the majority of patients have affected siblings or first-degree relatives. The diagnosis can be made through a physical examination, a patient history, and plain X-rays of the skeleton.
Presentation
The clinical presentation of Dyggve-Melchior-Clausen syndrome (DMC), initially described approximately 50 years ago [1], is distinguished by a combination of several features that develop in early childhood [1] [2] [3] [4] [5] [6]:
- Skeletal changes - The most prominent feature of DMC syndrome is a very short stature, with standard deviation scores (SDS) reaching as low as -12.6 SD in some reports [1]. The upper part of the body seems to be more severely affected and a pigeon-shaped (or barrel) chest is one of the hallmarks of Dyggve-Melchior-Clausen syndrome [1]. Rhizomelic limb shortening is an accompanying feature [1] [3]. Lumbar lordosis, brachydactyly, and broad interphalangeal joints are seen in up to 100% of patients, whereas scoliosis, kyphosis, protrusion of the sternal bone, genu valgum or varum, and limited joint extension are other notable manifestations that develop in up to 50% of individuals [1] [6].
- Mental retardation - The second crucial feature of DMC syndrome is mental retardation, varying from moderate to severe [1].
- Craniofacial changes - Virtually all patients who suffer from DMC syndrome develop microcephaly and a disproportionate development of the skull and facial bones compared to the brain size [1] [5]. In addition, characteristic facial changes include a narrow forehead, thick lips, macrognathia, prominent ears, and macrostomia [1].
Other notable findings are a protruded abdomen and generalized hirsutism [1].
Workup
Because Dyggve-Melchior-Clausen syndrome is very rare, the diagnosis may be difficult to attain without a thorough diagnostic workup. Since affected children develop the typical clinical presentation in the first several years of life, the physician should first obtain a detailed patient history from the parents. The history should cover the onset of symptoms and their progression, as well as severity. The fact that many identified patients either come from consanguineous marriages or have first-degree relatives who already suffer from Dyggve-Melchior-Clausen syndrome makes a complete family history crucial for identifying a genetic background of the disease. As soon as clinical suspicion is raised, imaging studies should be employed. Plain radiography of the axial skeleton, the pelvis, and the limbs is the key step for determining the exact type of deformity [1] [3]. One of the most specific findings seen in this syndrome is the lace-like character of the iliac crests. Small iliac wings, bilateral hip dislocation, a widened pubic symphysis, acetabular hypoplasia, a wide sacroiliac joint and deformed femoral heads are other prominent findings in the hips in these patients [1] [3]. A barrel-shaped chest with broad ribs, platyspondyly, and a double-hump shape of the bone end-plates provide sufficient evidence to make a solid diagnosis of Dyggve-Melchior-Clausen syndrome [1] [3]. Genetic studies can be used as a definitive method, which confirm mutations of the dymeclin gene located on chromosome 18 [1] [2] [4] [5] [6].
Treatment
There is no cure for DMC, so treatment focuses on managing symptoms and improving quality of life. This may involve a multidisciplinary approach, including orthopedic care to address skeletal issues, physical therapy to improve mobility, and educational support for developmental delays. Regular monitoring by healthcare professionals is essential to address any emerging complications.
Prognosis
The prognosis for individuals with DMC varies depending on the severity of symptoms. While skeletal abnormalities and intellectual disability are lifelong challenges, many individuals can lead fulfilling lives with appropriate support and management. Life expectancy may be slightly reduced due to potential complications, but with proper care, individuals can achieve a good quality of life.
Etiology
DMC is caused by mutations in the DYM gene, which plays a crucial role in the development and maintenance of cartilage and bone. The condition is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the mutated gene (one from each parent) to develop the syndrome. Parents of an affected child are typically carriers, meaning they have one copy of the mutated gene but do not show symptoms.
Epidemiology
DMC is an extremely rare condition, with only a few hundred cases reported worldwide. It affects both males and females equally and has been identified in various ethnic groups. Due to its rarity, the exact prevalence is not well established, but it is considered a very uncommon genetic disorder.
Pathophysiology
The pathophysiology of DMC involves disruptions in the normal development and function of cartilage and bone due to mutations in the DYM gene. This gene is crucial for the production of proteins involved in the structure and function of the Golgi apparatus, a cellular organelle important for processing and transporting proteins. The dysfunction of this process leads to the skeletal and neurological manifestations of the syndrome.
Prevention
As a genetic disorder, there is no known way to prevent DMC. However, genetic counseling can be beneficial for families with a history of the condition. Prospective parents who are known carriers of the DYM gene mutation may consider genetic testing and counseling to understand the risks and options available for family planning.
Summary
Dyggve-Melchior-Clausen Syndrome is a rare genetic disorder characterized by skeletal abnormalities and intellectual disability. It is caused by mutations in the DYM gene and inherited in an autosomal recessive pattern. While there is no cure, a multidisciplinary approach can help manage symptoms and improve quality of life. Genetic counseling is recommended for affected families to understand the condition and explore family planning options.
Patient Information
For patients and families affected by DMC, understanding the condition is crucial. It is important to work closely with healthcare providers to manage symptoms and access appropriate support services. Regular medical check-ups, physical therapy, and educational interventions can help individuals with DMC achieve their full potential. Families are encouraged to seek genetic counseling to learn more about the condition and discuss any concerns regarding family planning.
References
- Aglan MS, Temtamy SA, Fateen E, Ashour AM, Eldeeb K, Hosny GA. Dyggve–Melchior–Clausen syndrome: clinical, genetic, and radiological study of 15 Egyptian patients from nine unrelated families. J Child Orthop. 2009;3(6):451-458.
- Dyggve HV, Melchior JC, Clausen J. Morquio-Ullrich’s disease: an inborn error of metabolism? Arch Dis Child. 1962;37:525–534.
- Beighton P. Dyggve–Melchior–Clausen syndrome. J Med Genet. 1990;27:512–515.
- Thauvin-Robinet C, El Ghouzzi V, Chemaitilly W, et al. Homozygosity mapping of a Dyggve–Melchior–Clausen syndrome gene to chromosome 18q21.1. J Med Genet. 2002;39:714–717.
- Ehtesham N, Cantor RM, King LM, et al. Evidence that Smith–McCort dysplasia and Dyggve–Melchior–Clausen dysplasia are allelic disorders that result from mutations in a gene on chromosome 18q12. Am J Hum Genet. 2002;71:947–951.
- Gupta V, Kohli A, Dewan. Dyggve melchior clausen syndrome. Indian Pediatr. 2010;47(11):973-975.