Cornelia de Lange syndrome

1-day-old infant girl, born at term to a 33-year-old gravida 2, para 1 mother via vaginal delivery after spontaneous rupture of membranes (Apgar scores of 5 and 7 at 1 and 5 minutes, respectively), had mild respiratory distress. She had a healthy 4-year-old sibling. Chest x-ray films showed an enlarged heart. Cardiac echocardiogram showed a large intramural tumor filling virtually the entire left ventricle. There was also a left-sided abdominal mass. Ultrasound showed a normal-sized right kidney and a large, homogeneous, left-sided renal mass that lacked the echogenicity characteristic of renal tissue. A normal left adrenal gland was displaced superiorly. The liver showed no cystic changes. Head ultrasound was normal. A needle biopsy of the abdominal mass to rule out a "small, blue cell tumor of childhood" showed fibrosis and benign tubular elements. The infant died the day of birth due to cardiac failure. At autopsy, the left-sided abdominal mass was identified as an enlarged kidney (10 X 8.5 X 5 cm) with a preserved outline, but with a spongelike appearance due to numerous, round, cystic spaces, which measured up to 2 mm and were evenly distributed (bisected specimen, Figure 1). A low-magnification scanning electron micrograph (original magnification X20, Figure 2) showed multiple, variably sized cystic spaces with glomeruli somewhere along the cyst walls (little arrows) and the capsule (bottom right). At higher magnification (original magnification X200, Figure 3), the cells covering Bowman's capsule were abnormally tall and columnar (big arrows). The irregular surface in the depth of the dilated Bowman's space indicated foci of hyperplasia (curved arrows) with epithelial cells piling up. The glomerulus (fat arrow) was covered by abnormally plump, irregular podocytes. The tall columnar cells lining the Bowman's capsule showed a characteristic eosinophilic granularity of the cytoplasm (big arrows) when stained with hematoxylineosin and viewed under the light microscope (original magnification X400, Figure 4).

What is your diagnosis?

Pathologic Diagnosis: Glornerulocystic Kidneys of Tuberous Sclerosis

The enlarged kidney showed expansion of the cortex due to formation of glomerular cysts, as nicely demonstrated by the scanning electron micrographs. The one characteristic light microscopic finding unique for glomerulocystic kidneys of tuberous sclerosis is the hyperplastic change of Bowman's epithelium and epithelium in tubuli; those cells feature ample granular cytoplasm and sometimes fill the tubular lumen owing to excessive proliferation.1 Additional findings included vascular dysplasia (abnormal smooth muscle hyperplasia in vascular walls) and metanephric hamartomata. The large mass in the heart turned out to be a cardiac rhabdomyoma, which extended from the base of the heart toward the apex along the anterior left ventricular wall into the interventricular septum, with fingerlike projections toward the apex. This mass was the cause of significant obstruction to the outflow tract, leading to right-to-left shunting through a patent ductus arteriosus with retrograde filling of the coronary arteries and cardiac failure. The liver was normal on gross and microscopic examination. On thorough examination of the brain, small nests of subependymal giant cell tumors were found along the wall of the ventricles.

COMMENT

The changes seen in glornerulocystic disease of the kidney are one example of the hamartomatous changes that can be seen with tuberous sclerosis. All of the changes seen in tuberous sclerosis are hamartomatous, that is, changes leading to overgrowth or atypical growth of one or several components indigenous to a site, but growing in a disorganized or insufficiently controlled manner. In retrospect, this was a rather characteristic case of tuberous sclerosis presenting with cardiac rhabdomyoma.

In 1862, von Recklinghausen2 (without being aware of all the implications) described a similar case, an infant with cardiac rhabdomyomas and peculiar sclerotic brain lesions who died within a few hours after birth. His was the first case on record. In 1880, Bourneville3 referred to those lesions as sclerotic "tubers," hence the syndrome is called tuberous sclerosis or Bourneville syndrome. Subsequently, a wide spectrum of possible findings was described. Investigators realized that this is an inherited syndrome with an autosomal-dominant mode of inheritance and highly variable clinical presentation, ranging from fully expressed with all characteristic clinical findings to more subtle expression with only a few clinical findings. Sometimes the diagnosis is not made until adult life because characteristic changes develop later on in life. Obscuring the clinical picture is also the fact that the disease is the result of a spontaneous mutation in at least 60% of all cases; therefore, family history may not be contributory.

Tuberous sclerosis affects up to 1 in 6000 individuals. Two genes are known to cause the syndrome. The gene products are also known: the TSC1 gene, located on chromosome 9q34, contains 23 exons, and is used as the template for an 8.6-kilobase (kb) transcript encoding for a 1.164 amino acid protein.4 called hamartin, and the TSC2 gene, located on chromosome 16q13, contains 41 exons, and is used as the template for a 5.5-kb transcript encoding for a predicted 1.784 amino acid protein5 called tuberin. Loss of heterozygosity for both TSC1 and TSC2 has been demonstrated in hamartomatous lesions, and a growth suppressor-like function of the normal gene products is suggested. Abnormal TSC gene products from either site are sufficient to promote hamartomatous cell growth6 and have overlapping phenotypic effects. Interestingly, there must be a loss of function of both alleles for hamartomatous lesions to form (double-hit hypothesis), and at the cellular level, the tuberous sclerosis genes show autosomal recessive behavior. Less is known about the possible functions of hamartin than about those of tuberin. The latter has a domain with homology to a Rasrelated guanosine triphosphatase (GTPase) activating protein (GAP) for downstream targets rap1 and rab5. The spectrum of physiological functions, however, remains largely undefined. Hamartin and tuberin colocalize in the Golgi apparatus and show in vivo association via predicted coiled-coil domains, suggesting that both proteins function in the same complex rather than in separate pathways,7 thus offering an explanation for the overlapping pleiotropic phenotypic effects of 2 separate genes. A similar mechanism exists in patients with adult polycystic kidney disease, in which 2 separate genes on chromosomes 16p13.3-p13.12 (PKD1) and chromosome 4q21-23 (PKD2) somehow lead to formation of cysts. A subgroup of patients with tuberous sclerosis presenting with severe infantile polycystic kidney disease has large deletions, disrupting adjacent TSC2 and PKD1 genes and leading to inactivation of the PKD1 gene. This is in contrast to patients with autosomal dominant polycystic kidney disease, for which abnormal transcripts for PKD1 have been detected.8

Tuberous sclerosis presenting in infancy with unilateral polycystic kidney disease is unusual, but has been reported previously.9 The finding of seemingly isolated, severe glornerulocystic kidney disease in a patient who later developed skin lesions characteristic of tuberous sclerosis raises the question of whether some cases of seemingly isolated glomerulocystic kidney disease might in fact be unrecognized cases of tuberous sclerosis.

The term glomerulocystic kidneys is descriptive in nature and is defined histopathologically as kidneys with glomerular cysts.10 It is prudent to reserve the term glomerulocystic kidney disease for nonsyndromal cases with severely cystic kidneys. There are 4 subgroups of glomerulocystic kidney disease: autosomal dominant polycystic kidney disease in young infants, dominant glomerulocystic kidney disease in older patients, familial hypoplastic glomerulocystic kidney disease, and sporadic nonsyndromal glomerulocystic kidney disease. The term glomerulocystic kidneys should be applied to the entire heterogeneous group, comprising cases of complex inheritable malformation syndromes in which glomerular cysts are a major component (tuberous sclerosis; orofaciodigital syndrome, type 1; brachyrnesomelia-renal syndrome; trisomy 13; short rib-polydactyly syndromes, Majewski and SaldinoNoonan type; Jeune asphyxiating thoracic dystrophy syndrome; Zellweger cerebro-hepato-renal syndrome; and familial juvenile nephronophthisis) or a minor component (congenital nephrotic syndrome, Cornelia de Lange syndrome, Down syndrome, Marden-Walker syndrome, phocomelia syndrome, Smith-Lemli-Opitz syndrome, trisomy 9, and trisomy 18). There is also a small number of dysplastic kidneys, hereditary or sporadic, in which glomerular cysts are relatively minor components of major renal maldevelopment, namely, diffuse cystic dysplasia associated with renal-hepatic-renal dysplasia and glutaric aciduria, type 2; Meckel syndrome; Goldston syndrome; and short rib-polydactyly syndromes, which may be accompanied by renal dysplasia as facultative component.

References

1. Bernstein], Robbins TO, Kissane JM. The renal lesions of tuberous sclerosis. Semin Diagn Pathol. 1986;3:97-105.

2. von Recklinghausen F. Ein Herz von einem Neugeborenen, welches mehrere Theils nach aussen, Theils nach den Hohlen prominierencle Tumoren trug. Monatsschr Geburtsk. 1862;20: 1.

3. Bourneville D. Sclereuse tubereuse des circonvolutions cerebrales: idiotie et epilepsie hemiplegique. Arch Neurol (Paris). 1880;1:81.

4. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277(5327): 805-808.

5. European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterisation of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305-1315.

6. Carbonara C, Longa L, Grosso E , et al.Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. Genes Chromosom Cancer 1996; 15:18-25.

7. van Slegtenhorst M, Nellist M, Nagelkerken B , et al. Interaction between hamartin and tuberin, theTSC1 and TSC2 gene products. Hum Mol Genet. 1998; 7:1053-1057.

8. Brook-Carter PT Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease: a contiguous gene syndrome. Nat Genet. 1994;8:328-332.

9. Miller ID, Gray ES, Lloyd DL. Unilateral cystic disease of the neonatal kidney: a rare presentation of tuberous sclerosis. Histopathology. 1989;14:529-532.

10. Bernstein J. Glomerulocystic kidney disease: nosological considerations. Pediatr Nephrol. 1993;7:464-470.

Accepted for publication May 17, 1999.

From the Department of Pathology, Children's Memorial Hospital and Northwestern University Medical School, Chicago, Ill. Dr Senger in now with The Hospital for Sick Children, Toronto, Ontario, Canada.

Reprints not available from the author.

Copyright College of American Pathologists Feb 2000
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