¹Medellin Colombia,  and Nashville, TN

Background: First described in 1914 ^[1] . It is a rare congenital syndrome caused by a peroxisomal dysfunction^{1, [2] , [3]} . It is one of the four syndromes of the  “peroxisome biogenesis disorders” resulting from anomalous enzymatic function of the metabolism of the fatty acids³ .

Overall incidence:  1:10.000 live births^{3, [4]} .

Definition: Erratic cartilage calcification during growth which produces the heterogeneous group of disorders that results in small ossification centers in the epiphyseal cartilage of the long bones and spine, skin lesions, cataracts, craniofacial dysmorphism, joint contractures^1,3 , and cardiac malformation^{1, [5]} . In surviving children, abnormal growth leads to dysmorphism, kyphoscoliosis, limb shortness, and luxation of the hip^{1,3,5 .}

Classification:

• Autosomal dominate type (non rhizomelic)

• Autosomal recessive type (rhizomelic)

• X- linked dominant type

• X- linked recessive type

• Sheffield, mild type

• Other variants

AUTOSOMAL DOMINANT TYPE  (Non rhizomelic, nonlethal, type)

Synonyms:  Dysplasia epiphysealis congenita, stippled epiphyses, chondrodysplasia punctata dominant type, chondrodysplasia epiphysealis punctata, chondrodystrophia calcificans congenita, Conradi-Hunermann syndrome^{3,[6] ,[7]<![endif]>} .

Frequency:  It is the most common of all chondrodysplasia punctata^5,6 ; most are new mutations (11 families reported).

Etiology:  Autosomal dominant inheritance⁵ .

Pathogenesis:  Unknown⁵ .

Sex ratio:  M3:F1⁵ .

Major diagnostic criteria:

• Craniofacial dysmorphism:  asymmetric head, frontal bossing; flat nasal bridge; dysplastic auricles; mongoloid palpebral fissures; hypertelorism; high arched palate.
• Ocular abnormalities: cataract; corneal opacity; nystagmus; microphthalmos; microcornea; glaucoma; and dislocated lens.
• Cutaneus abnormalities:  ichthyosis and hyperkeratosis; alopecia; layered and split nails.
• Skeletal abnormalities:  asymmetric mild shortening of all long bones; bowing; stippled epiphysis; vertebral scoliosis, clefting; or wedging; flexion contracture of the joints; clubfoot or valgus deformity.
• Others:  short neck; pulmonic artery stenosis; ascites; polyhydramnios^3,4,5,6 .

However, prenatal diagnosis has been uncommonly reported [8] .

Radiologic findings:  Mild shortening of all long bones with multiple epiphyseal punctate calcific deposits in the infantile cartilaginous skeleton, which may or may not be seen by ultrasound after 14 weeks. Vertebral body deformities and scoliosis can also be seen^3,4,5,6 . Stippling of the proximal humerus may also help to identify the condition [9] .

Differential diagnosis:  Other forms of CP; warfarin embryopathy; alcohol embryopathy; Zellweger syndrome, multiple epiphyseal dysplasias⁶ .

Associated findings:  Mild mental retardation and postaxial polydactyly has been rarely described⁵ . Complex congenital cardiac disease and central nervous system anomalies have also been reported in one girl⁹ .

Gene mapping and linkage:  Unknown⁵ .

Prognosis:  Excellent.  Affected individuals usually have normal life span and intelligence^{5, [10]}

AUTOSOMAL RECESSIVE TYPE (Rhizomelic, lethal or sublethal type)

Synonyms:  The same as for the autosomal dominant type^5,6 .

Frequency:  Common: 0.1:10.000 live birth⁶

Etiology:  Autosomal recessive inheritance⁵ .

Pathogenesis:  Peroxisomal disorder with severe deficiency of plasmalogens and deficient activity of the peroxisomal enzyme acyl-CoA dihydroxy-acetone-phosphate acyltransferase in cultured cell fibroblasts^{1,2, [11] , [12] , [13]} . Pathological examination of the long bones shows disruption of the growth plates, foci of calcification, cyst formation, and zones of inflammation. The changes probably reflect some damage during development with subsequent healing of the cartilage by fibrosis, calcification and ossification. The clefts of the vertebral bodies are due to the embryogenic arrest of development. The microcephaly is related to a decrease in the number of nerve cells found in neurohistologic examinations^5,6 .

Sex ratio:  M1:F1⁵ .

Potential sonographic findings:

• Skeletal: mild punctuate (stippled) calcific deposits in cartilaginous axial skeleton; symmetric rhizomelic short limb dwarfism; joint contractures; foot deformities; bowing of proximal limbs.
• Craniofacial: flat face; microcephaly; micrognathia; cataracts; cleft palate.
• Cutaneous abnormalities: ichthyosis.
• Congenital heart disease.

Radiologic findings:

• Symmetric shortening of the proximal bones.
• Punctate calcific deposits in infantile cartilaginous skeleton.
• Coronal clefts in the vertebra^6,10 .

Other findings:  Lymphedema of the cheeks; alopecia; pulmonary hypoplasia; umbilical cord hernia; mental retardation; facial paralysis^6,10 ; hypoplasia of the thymus (Di George anomaly)¹² ; recurrent infections⁹ .

Differential diagnosis:  Other forms of chondroplasia punctata; warfarin embryopathy; alcohol embryopathy; Zellweger syndrome; multiple epiphyseal dysplasias; trisomies 13 and 18⁶ .

Gene mapping and linkage: Unknown⁵ .

Prognosis:  Most fetuses die in utero or shortly thereafter, and the few that survive suffer severe debility and profound mental retardation. Death ensues in the first decade of life^{6,10,13, [14]} .

X-LINKED DOMINANT TYPE

Synonyms:  Chondroplasia punctata: Conradi-Hunermann type subgroup B⁶ .

Incidence:  Very uncommon⁶ .

Etiology:  X-linked dominant inheritance, with possible lethality in the hemizygous male (Xp 22.32)⁵ .

Pathogenesis: Peroxisomal enzyme deficiency has been reported.

Sonographic findings:  Flat nasal bridge, frontal bossing, and asymmetric shortening of the limbs, flexion contractures, foot deformities, polydactyly, scoliosis, neck shortening and cataracts⁶ .

Differential diagnosis:  Other forms of chondrodysplasia punctata, warfarin embryopathy, alcohol embryopathy, Zellweger syndrome, and multiple epiphyseal dysplasias⁶ .

Prognosis:  Extremely variable, from neonatal death to bare detectability of the disorder in the adult⁷ .

Management:  Symptomatic⁵ .

X — LINKED RECESSIVE TYPE

Frequency:  Very rare:  two families, four patients⁶ .

Etiology:  X-linked recessive disorder with deletion of portion of the short arm of X chromosome⁶ .

Radiologic findings:  Resembles non rhizomelic type; diffuse stippling of epiphyseal, paravertebral, laryngeal, and tracheal areas; nasal hypoplasia; cataracts; ichthyosis; mild short stature; hypoplasia of the distal phalanges⁶ .

Sonographic findings: No specific information of prenatal sonographic diagnosis.

Differential diagnosis:  Other forms of chondrodysplasia punctata (specially Conradi- Hunermann type), warfarin embryopathy, alcohol embryopathy, Zellweger syndrome, and other forms of ichthyosis⁶ .

CHONDRODYSPLASIA PUNCTATA, SHEFFIELD TYPE

Synonym:  Chondroplasia punctata mild form.

Mode of inheritance: Not known⁶ .

Frequency:  Very few cases reported⁶ .

Clinical manifestations:  failure to thrive; mental retardation; typical facies with flattened tip of the nose and depressed nasal bridge⁶ .

Sex ratio: M1/F1.⁶

Radiologic findings:  stippling replacing ossification of calcaneus in infancy; hypoplastic and/or multi centered calcaneus in older life, sacral and coccygeal stippling (rarely in other areas); coronal and sagittal clefts in vertebrae⁶ .

Differential diagnosis:  Other forms of chondrodysplasia punctata, warfarin embryopathy, alcohol embryopathy, Zellweger syndrome, and other forms of ichthyosis; chromosome 18 and 21 syndromes⁶ .

References:

[1] Karoutsos S, Lansade A, Terrier G, Moulies D. Chondrodysplasia punctata and subglottic stenosis. Anesth Analg. 1999 Nov;89(5):1322-3.

[2] Steinberg SJ, Elcioglu N, Slade CM, Sankaralingam A, Dennis N, Mohammed SN,Fensom AH. Peroxisomal disorders: clinical and biochemical studies in 15 children andprenatal diagnosis in 7 families. Am J Med Genet. 1999 Aug 27;85(5):502-10.

[3] Callen PW, Ultrasonography in Obstetrics and Gynecology . 4th edition. Phyladelphia, Pensylvania, W B Saunders Co. 2000.

[4] Sherer DM, Glantz JC, Allen TA, Lonardo F, Metlay LA .Prenatal sonographic diagnosis of non-rhizomelic chondrodysplasia punctata. Obstet Gynecol. 1994 May;83(5 Pt 2):858-60.

[5] Buyse ML: Birth Defect Encyclpedia. Cambridge, England, Blackwell Scientific, 1990.

[6] Taybi H, Lachman RS; Radiology of S?ndromes, Metabolic disorders, and squeletal Dysplasias. St. Louis,    Mosby Yearbook,1996.

[7] Tuck SM, Slack J, Buckland G. Prenatal diagnosis of Conradi"s syndrome. Case report. Prenat Diagn. 1990 Mar;10(3):195-8.

[8] Pryde PG, Bawle E, Brandt F, Romero R, Treadwell MC, Evans MI. Prenatal diagnosis of nonrhizomelic chondrodysplasia punctata (Conradi-Hunermann syndrome).Am J Med Genet. 1993 Sep 1;47(3):426-31.

[9] Duff P, Harlass FE, Milligan DA. Prenatal diagnosis of chondrodysplasia punctata by sonography. Obstet Gynecol. 1990 Sep;76(3 Pt 2):497-500.

[10] Argo KM, Toriello HV, Jelsema RD, Zuidema LJ.Prenatal findings in chondrodysplasia punctata, tibia-metacarpal type. Ultrasound Obstet Gynecol. 1996 Nov;8(5):350-4. Review.

[11] Brookhyser KM, Lipson MH, Moser AB, Moser HW, Lachman RS, Rimoin DL.Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated.

[12] Sastrowijoto SH, Vandenberghe K, Moerman P, Lauweryns JM, Fryns JP. Prenatal ultrasound diagnosis of rhizomelic chondrodysplasia punctata ii a primigravida.Prenat Diagn.1994Aug;14(8):770-6inaprimigravida.Prenatiagn.1994Aug;14(8):770-6

[13] Hoefler S, Hoefler G, Moser AB, Watkins PA, Chen WW, Moser HW. Prenatal diagnosis of rhizomelic chondrodysplasia punctata.Prenat Diagn. 1988 Oct;8(8):571-6.

[14] Hertzberg BS, Kliewer MA, Decker M, Miller CR, Bowie JD. Antenatal ultrasonographic diagnosis of rhizomelic chondrodysplasia punctata. J Ultrasound Med. 1999 Oct;18(10):715-8