Chondrodysplasia Punctata

Refers to a heterogeneous group of disorders having in common ichthyosis and bony abnormalities probably as a result of abnormalities of steroidal biosynthesis. The international nomenclature and classification of osteochondrodysplasias categorized the subtypes of chondrodysplasia punctata as (1) rhizomelic type, (2) Zellweger syndrome, (3) Conradi-Hünermann type, (4) X-linked recessive type, (5) brachytelencephalangic type, (6) tibial-metacarpal type, (7) vitamin K-dependent coagulation defect, and (8) other and acquired genetic disorders including warfarin embryopathy. Specific features of the most common individual types of chondrodysplasia punctata are given below.

Toriello-Higgins-Miller Syndrome; Chondrodystrophia Calcificans Congenita: Congenital Stippled Epiphyses.

For rhizomelic chondrodysplasia punctata type I, the incidence in the general population has been estimated to be 1:100,000.

Inherited as a sex-linked recessive trait and caused by a mutation in the arylsulfatase E (ARSE) gene. Known genes are located on Xp22.3 and Xp11.23-p11.22. Other syndromes can be inherited in an autosomal dominant or recessive fashion.

Made clinically based on radiologic signs (calcified stippling of the hyaline cartilage and bones presenting in infancy and disappearing at 2-3 years of age) associated with multiple clinical signs such as limbs with short segments, dysmorphism with a hypoplastic nasal root, skin lesions, and cataracts. Laboratory assays can be used to demonstrate a deficiency in red blood cell plasmalogen, elevated plasma concentration of phytanic acid (although this depends on the food intake), and deficient plasmalogen biosynthesis and phytanic acid oxidation in skin fibroblasts.

This disorder is often associated with prematurity and can be lethal in early infancy. Hypotonia and asymmetry of the body are frequent. Other clinical features can involve the head and neck (brachycephaly, short neck, flat face, frontal bossing, coloboma of the iris, cataract, nystagmus, optic disc anomaly, flattened small nose with anteverted nares, partial absence of the mandible, short columella, long philtrum, tented upper lip, low-set ears with conductive deafness), the limbs (proximal shortening of humeri and femora [rhizomelia], micromelia, epiphyseal anomalies, punctate calcifications of epiphyses, bowed diaphysis, brachydactyly, clinodactyly of the fifth finger, short great toe, small foot, metacarpal anomalies, dislocated hip and restricted joint mobility), the skeleton (flat cheek bones, punctate vertebrae, spina bifida occulta, abnormal vertebral size, pectus excavatum scoliosis), and the skin (absent scalp hair, ichthyosis, cutis marmorata, hypoplastic toenails). Other features that have been described are congenital cardiac lesions, respiratory distress, laryngeal abnormalities, dysplastic kidneys, hydronephrosis and megaureter, abnormal genitalia, splenomegaly, and liver enlargement.

Rhizomelic Chondrodysplasia (RCDP)

Most often, this disorder is inherited in an autosomal recessive and rarely in an X-linked recessive fashion. It is caused by multiple peroxisomal abnormalities. Peroxisomes are ubiquitous cellular organelles involved in different cellular functions, such as β-oxidation of very-long-chain fatty acids (VLCFA), production of plasmalogen (involved in cell membrane integrity) and bile acids, gluconeogenesis, catabolism of purines and polyamines, and ethanol metabolism. The defect can be caused by either abnormally formed peroxisomes associated with several peroxisomal dysfunctions or by a defect involving only a single peroxisomal protein with normal peroxisomal structure. Based on biochemical findings, three forms of RCDP can be distinguished. In RCDP I, the defective gene has been identified as PEX7, which encodes for the peroxisomal type 2 targeting signal receptor (PTS2) and maps to 4p16-p14. The PTS2 defect affects multiple enzymes (peroxisomal 3-ketoacyl-CoA thiolase, alkyl-DHAP [dihydroxy acetone phosphate] synthase, DHAP-acyltransferase, and phytanoyl-CoA-hydroxylase). In RCDP II and III, the PEX-7 protein is normal, but a mutation affects the structural gene responsible for the specific enzyme, that is, dihydroxy acetone phosphate acyltransferase deficiency in RCPD II and alkyl-DHAP synthase deficiency in RCDP III. The plasmalogen level in erythrocytes is abnormal in all three types of RCDP. Enzyme activity measurements can be used to reliably diagnose RCDP prenatally. Clinical features are variable and may include congenital cataracts, micrognathia, cleft palate, low and broad nasal bridge, anteverted nares, respiratory insufficiency, short stature, rhizomelic limb shortening, metaphyseal splaying, joint contractures, vertebral anomalies (coronal clefting and kyphoscoliosis), failure to thrive, ichthyosis, cortical atrophy, delayed myelination (a result of deficiency of plasmalogens), seizures, sensorineural deafness, and severe mental retardation. The developmental quotient often is below 30. Although delayed, early developmental skills such as smiling and recognizing voices are achieved by most children. However, these children normally do not achieve the skill level of normal children 6 months of age. Because of the severe neurologic compromise, recurrent aspirations with recurrent respiratory tract infections are common. The chest may be small with restricted compliance. Cervical canal stenosis has been described in these patients and may result in tetraplegia. In more than half of the patients, death occurs before 2 years of age.

Conradi-Hünermann Syndrome

(Synonym: X-Linked Dominant Type of Chondrodysplasia Punctata): This form is caused by mutations in the delta-8-delta-7-sterol isomerase/emopamil binding protein and has been mapped to Xp11.23-p11.22. Clinical features are extremely variable and may include failure to thrive and anomalies of the head (Dandy-Walker malformation, ventriculomegaly, microphtalmus, glaucoma, cataracts, nystagmus, flat face, frontal bossing, and unilateral facial hypoplasia), the skeleton (short stature with asymmetric limb shortening, short neck, hemivertebrae, kyphoscoliosis, patellar dislocation, bilateral club feet), the skin (ichthyosis and “orange peel" skin, alopecia), the kidneys (hydronephrosis), and the lungs (tracheal calcifications and stenosis, restrictive lung disease with frequent respiratory complications). These patients may be mentally normal, however mild to moderate mental retardation has also been described. Atropine is contraindicated in patients with glaucoma. This syndrome has been related to CHILD syndrome.

Obtaining a full history and complete physical examination are imperative. Given the anatomical features of the disease, the patient needs to be carefully evaluated for possible difficulties in airway management. Evaluate cardiac (electrocardiogram, echocardiography) and renal function (creatinine, blood urea nitrogen) if necessary. Evaluate respiratory function (clinically, chest radiographs, pulmonary function tests, and arterial blood gas analysis).

Tracheal intubation can be difficult because of mandibular and laryngeal anomalies. Maintain spontaneous ventilation until the airway has been secured. Have smaller endotracheal tube sizes ready because of possible tracheal stenosis. Careful intraoperative positioning is required, but can be difficult because of multiple malformations. Because of the frequency of respiratory distress, particularly in neonates and infants, close perioperative (respiratory) monitoring is mandatory. Prolonged postoperative mechanical ventilation may be necessary. Regional anesthesia is not contraindicated but can be difficult to achieve. Venous and arterial access is often challenging. Consider the risk of dehydration in patients with severe ichthyosis.

Muscle relaxants are not contraindicated, but should not be used before the airway has been secured. Subacute bacterial endocarditis prophylaxis may be required. Anesthetic drugs (particularly with predominantly renal elimination) and perioperative fluid management may require adaptation to renal function. However, it should be kept in mind that ichthyosis may result in increased fluid losses.

Neuronal Ceroid Lipofuscinoses: A group of hereditary progressive neurodegenerative disorders with mental retardation, visual loss, and seizures. The neuronal ceroid lipofuscinoses probably are the most common class of neurodegenerative disease in children.