Cartilage-Hair Hypoplasia Syndrome

A form of severe short-limbed dwarfism with hair anomalies, defective immunity, and erythrogenesis.

Metaphyseal Chondrodysplasia McKusick type.

First recognized as a distinct entity in the Old Order Amish, a religious group in the United States, in 1965 by the American geneticist V.A. McKusick, who is also the founder and one of the editors of the “Online Mendelian Inheritance in Man" (OMIM) database.

Clustering is found in Old Order Amish (1-2 in 1000 live births) and in certain areas of Finland (1 in 23,000 live births). It is very rare in other populations. No sexual predilection.

Autosomal recessive with reduced penetrance. Caused by mutations of the mitochondrial RNA-processing endoribonuclease gene, which is located on 9p21-p12. This enzyme is responsible for cleavage of RNA in the mitochondrial DNA synthesis and for nucleolar cleaving of pre-rRNA.

Defective cellular proliferation has been described affecting predominately T-cells (resulting in lymphopenia in almost two thirds of patients), but also involves B-cells (low serum concentrations of immunoglobulins A and/or G; in approximately one third of patients), neutrophils, and fibroblasts. This syndrome has been suggested to result from a generalized defect in cellular proliferation.

Incomplete extension in the elbows, anterolateral chest deformity, genua varum, and excessive distal length of the fibula relative to the tibia are specific skeletal features. The major radiologic abnormalities are confined to the metaphyseal regions of tubular bones. Biopsy shows hypoplasia of cartilage to be the nature of the skeletal abnormalities.

Radiographs show metaphyseal dysostosis. The disorder may involve the cervical spine (odontoid hypoplasia), the skeleton (short stature secondary to dwarfism with an adult height usually <135 cm, flaring of the lower rib cage at the costochondral junction, scoliosis, lumbar hyper-lordosis, platyspondylia, narrowed interpeduncular distances, small pelvic inlet, limited elbow extension, metaphyseal dysplasia, fibular length exceeding tibial length distally, short hands, brachydactyly, joint hyperextensibility), the viscera (Hirschsprung disease, esophageal atresia, anal stenosis, malabsorption), the teeth (microdontia, anomalies of the incisors and premolars), and the hair and skin (sparse, fine, light colored hair, redundant skin folds around the neck and the extremities, hypopigmentation, onychodysplasia). Laboratory investigations may show macrocytic anemia, neutropenia, lymphopenia, and cellular immunodeficiency. Recurrent pulmonary and opportunistic infections in these patients are common (mainly Candida albicans, Pneumocystis carinii, and Cytomegalovirus). Patients are predisposed to a severe course of Varicella infection (multiple fatalities have been reported) and malignancies (in approximately 5% of patients, mainly non-Hodgkin lymphomas). Susceptibility to infections usually improves in adulthood. The higher mortality in these patients compared to the general population mainly refers to children and is a result of the compromised immune system.

Obtain a complete blood count with differentiation of red and white cells. The degree of anemia may correspond to the degree of immune deficiency. Anemia usually is mild, however, severe forms of hypoplastic anemia of childhood have been reported. Assess the airway for difficult intubation. Recurrent pulmonary infections warrant careful evaluation of pulmonary function (chest radiograph, arterial blood gas analysis, pulmonary function test). Check cardiac function to delineate the extent of cardiac compromise secondary to chest deformities and scoliosis (electrocardiography, echocardiography). If any concerns exist regarding the stability of the cervical spine, radiologic examinations should be performed.

Strict aseptic technique during insertion of lines, performance of any regional blocks, and other invasive procedures is mandatory in the presence of immune deficiency. Lumbar spinal or epidural anesthesia may be difficult because of scoliosis, pronounced lumbar lordosis, and diminished interpeduncular distance. Venous access often is difficult because obesity is frequent in these patients. A very short neck (and potentially unstable cervical spine) may make access to the jugular vein difficult or impossible. In addition, exposure of the larynx may prove extremely difficult during conventional laryngoscopy in some patients with dwarfism secondary to a very short neck. In-line stabilization and extreme care are required for intubation of patients with unstable cervical spine. Alternatively, fiberoptic intubation (awake or asleep) may be used. Cases of significant ventilation problems secondary to tracheobronchial malacia with tracheal collapse on induction of anesthesia have been reported. Careful handling of the anomalous teeth is recommended to prevent dislocation. Patients with respiratory compromise often require postoperative mechanical ventilation, especially in the presence of thoracic deformities. Respiratory or metabolic acidosis may cause a profound rise in pulmonary artery pressures and should be avoided in patients with preexisting pulmonary hypertension. Hypercapnia (with respiratory acidosis) can easily result from inhalational anesthesia, and a manually assisted ventilation technique is recommended if difficult airway management is expected. Spontaneous ventilation must be preserved until the airway has been secured. Blood products must be irradiated in these patients to prevent a graft-versus-host reaction. Careful positioning secondary to skeletal anomalies with joint laxity is necessary.

An inhalation induction or awake-fiberoptic intubation should be performed in patients with anticipated airway difficulties and muscle relaxants avoided until the airway has been secured. Caution with attenuated live vaccines because of potential risk of severe infection.

Metaphyseal Chondrodysplasia, Jansen Type: An extremely rare progressive disorder in which portions of the bones of the arms and legs develop abnormally with unusual cartilage formations and subsequent abnormal bulbous metaphyses (metaphyseal chondrodysplasia). Affected individuals exhibit unusually short arms and legs and short stature (short-limbed dwarfism), findings that typically become apparent during early childhood. Infants with Jansen-type metaphyseal chondrodysplasia may have characteristic facial abnormalities and additional skeletal malformations. Hypercalcemia is present.

Metaphyseal Chondrodysplasia, Schmid Type: A very rare inherited disorder characterized by short stature with abnormally short arms and legs (short-limbed dwarfism). Other physical characteristics may include outward “flaring” of the lower rib cage, genua vara, pain in the legs, and/or hip deformities (coxa vara). Such abnormalities of the legs and hips typically result in an unusual “waddling” gait.