| Phenotype and clinics | The craniofacial appearance is essential to the diagnosis. Hydronephrosis is present in over 90% of cases. Other features, particularly skeletal findings, are helpful, but less specific. No generally accepted diagnostic guidelines exist.
Craniofacies: In addition to the pathognomonic "midface retraction" consisting of shallow orbits and midface hypoplasia with resulting prominence of the forehead, all reported patients have high forehead, large fontanelles and widely patent cranial sutures, particularly the metopic suture. The facial appearance is often described as coarse. Hypertelorism, flat nasal bridge, anteverted nares and lowset ears with protruding lobules are frequent. Nearly half the patients have choanal stenosis.
Central nervous system: Mental deficiency is usually profound. Both hypotonia and spasticity are common and may occur at different times in the same patient. Seizures of varying types, often including infantile spasms, are reported in most patients. Central nervous system malformations, particularly agenesis of the corpus callosum are reported occasionally, but the major anomaly on cranial MRI is cerebral atrophy which has been documented to progress over time in many of the longer surviving patients.
Skeletal: The skull base is steep, short, and often sclerotic with wide occipital synchondrosis, and multiple wormian bones. The ribs are broad and the clavicles are long. There is frequent hypoplasia of the first ribs, pubis, and distal phalanges. There is mild mesomelic shortening with widening of distal femur and increased density and broad cortex of the long bones. Additional limb anomalies such as polydactyly and talipes are found in a significant minority of patients.
Urogenital: Hydronephrosis on prenatal ultrasound is often the first abnormality noted. A few patients have died neonatally from lung hypoplasia related to either oligohydramnios sequence or compression from massive dilated kidneys. Virtually all patients have renal anomalies, primarily hydronephrosis, but only a few require treatment for obstructive lesions. Most patients have varying degrees of genital hypoplasia with hypospadias, micropenis and occasional ambiguous genitalia in males and labial hypoplasia, hymenal atresia and occasional bicornuate uterus in females.
Cardiac: About 1/3 of the patients have congenital heart disease, most commonly atrial septal defect. Ventricular septal defect, pulmonic stenosis, AV canal, and carctation have also been reported.
Dermatologic: Most patients have hypertrichosis, redundant nuchal skin, hypoplastic nipples, hyperconvex nails and hypoplastic dermal ridges. Facial hemangiomas are common.
Other: Alacrima, visual impairment, hearing loss, macroglossia. Gingival hyperplasia occurs in long-term survivors. |
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| | Gluteal area of same patient supine. Sacral asymmetry is due to a mass, which proved to be a primitive neurectodermal tumor. |
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| Neoplastic risk | Among 46 reported patients, 7 (15%) have had childhood tumors including 3 sacrococcygeal teratomas, 2 primitive neurectodermal tumors arising in the sacral area, 1 hepatoblastoma, and 1 Wilms tumor arising in a multicystic dysplastic kidney. Both of the latter tumors arose in older children (above age 2), raising concern that long term survivors need to be followed for possible tumor development. Because of early deaths and lack of follow-up reports for many patients, the reported incidence of tumors must be considered a minimal estimate. Among 15 patients known to have survived beyond age 2, three (20%) have had tumors. |
| Treatment | Treatment is entirely symptomatic and directed at complications. The profound central nervous system involvement is the major cause of morbidity and mortality. Seizures are frequent and difficult to control with many patients failing to respond to anticonvulsants or ketogenic diet. Several patients with hearing loss have had some benefit from hearing aids. Hydronephrosis is usually stable, and only a few patients have required surgery for obstruction. Patients with tumors have responded to standard care including surgery and/or chemotherapy. |
| Evolution | Facial features may become less characteristic in long-term survivors. Hydronephrosis rarely progresses to renal failure. Progressive gingival hyperplasia in older patients raises concern about a storage disease, but patients coming to autopsy do not have evidence of a lysosomal disorder. Unfortunately the neurologic status tends to deteriorate over time. Developmental delay is usually profound with most patients remaining non-ambulatory and non-verbal throughout their lives. Seizures can develop at any age and tend to become increasingly difficult to control. Patients who were hypotonic as neonates may develop severe spasticity. Follow-up MRI studies often show worsening cerebral atrophy and increasing ventriculomegaly without obstructive hydrocephalus. |
| Prognosis | Half of all reported patients were deceased at the time of the initial report. 20% died in the first year, another 17% in the second year and 13% between 2 and 10 years of age. Only 4 patients (<10%) are known to have lived beyond age 4 and all of these were severely cognitively impaired.. The most common cause of death is progressive neurologic deterioration resulting in pneumonia and other infections. Several patients died neonatally from respiratory distress related to massive nephromegaly. Two patients had local recurrences of cancer, but only one patient, a 9 year old with Wilms tumor, died from metastatic cancer. |
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