Medullary Cystic Disease Clinical Presentation

Updated: Nov 16, 2015
  • Author: Prasad Devarajan, MD, FAAP; Chief Editor: Craig B Langman, MD  more...
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Presentation

History

A family history of consanguinity, early death, or renal disease is present in 67% of patients with nephronophthisis (NPH).

In juvenile nephronophthisis (the most common form), the first symptoms usually develop around age 5 years and consist of polyuria and polydipsia. These symptoms are related to a reduced urinary concentrating capacity and loss of sodium conservation and occur early in the course of the disease, well before a reduction in glomerular filtration rate. Typically, the urine osmolarity is less than 400 mosm/kg in the first morning sample.

Children exhibit decreased growth velocity, initially related to chronic dehydration and subsequently confounded by renal insufficiency.

Features that distinguish nephronophthisis from medullary cystic kidney disease (MCKD) include the following:

  • The inheritance pattern is autosomal recessive.

  • The median age of onset of end-stage renal disease (ESRD) is 13 years in juvenile nephronophthisis, 1-3 years in infantile nephronophthisis, and 19 years in adolescent nephronophthisis.

Extrarenal associations of nephronophthisis include the following:

  • Cogan syndrome - Oculomotor apraxia

  • Senior-Loken syndrome - Retinitis pigmentosa

  • Mainzer-Saldino syndrome - Liver fibrosis, bone dysplasia

  • Joubert syndrome - Coloboma or retinal degeneration, nystagmus, ptosis, aplasia of cerebellar vermis with ataxia and psychomotor retardation, polydactyly, and neonatal tachypnea or dyspnea

  • Sensenbrenner syndrome - Cranioectodermal dysplasia and electroretinal abnormalities

Distinguishing features of medullary cystic kidney disease include the following:

  • The inheritance pattern is autosomal dominant.

  • The median onset of ESRD for medullary cystic disease type 1 is age 62 years and for medullary cystic kidney disease type 2 is age 32 years.

  • Extrarenal associations are restricted to hyperuricemia and gout.

The following conditions have renal histologic features similar to those of nephronophthisis:

  • Jeune syndrome or asphyxiating thoracic dysplasia - Small thorax, short limbs, and hypoplastic Iliac wings

  • Ellis-van Creveld syndrome - Chondroectodermal dysplasia

  • PHYNS syndrome - Retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia

  • Laurence-Moon-Bardet-Biedl syndrome - Retinitis pigmentosa, obesity, polydactyly, and mental retardation

In the case of MCKD, there is usually a family history of hyperuricemia and progressive kidney disease. Patients with MCKD type 2 (the more common form) present as adolescents or young adults with gout and chronic kidney disease, with a relatively bland urinalysis. Patients with MUC1 mutations typically present with slowly progressive chronic kidney disease and usually develop hyperuricemia later in life. Patients with REN mutations present with features similar to those with UMOD mutations, but additionally have manifestations of low renin and angiotensin (anemia out of proportion to the kidney disease, low blood pressure, hyperkalemia, and increased risk of volume depletion).

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Physical

The clinical findings are related to tubular injury that leads to a reduction in urinary concentrating capacity, renal sodium loss, and insidious but inevitable progression to renal failure. The tubular defects precede the decline in renal function and may be present in asymptomatic siblings with the disease.

Nephronophthisis and medullary cystic kidney disease share several clinical features. In most patients, the signs associated with decreased urinary concentration capacity are present by age 5 years. The signs include polyuria, polydipsia, enuresis, and dehydration. Common findings include a failure to thrive and weakness. Anorexia, nausea, pruritus, bone pain, and neurologic symptoms herald ESRD. Because of salt wasting, hypertension is rare, except in the infantile form of nephronophthisis.

Pallor is another characteristic finding. In contrast to other renal diseases in which the degree of anemia depends on the stage of renal insufficiency, in nephronophthisis, the severity of the anemia exceeds the degree of renal insufficiency. Anemia may occur before renal insufficiency develops. This normocytic and normochromic anemia is more severe than that of other chronic renal diseases and does not result from iron deficiency or hemolysis.

Studies have shown that, in patients with nephronophthisis, the serum erythropoietin (EPO) concentration is lower than that of patients with other progressive renal diseases. EPO is a glycoprotein hormone that controls the differentiation of erythroid progenitor cells in the bone marrow and the production of erythrocytes. After birth, EPO is produced mainly in the kidneys, specifically in the peritubular fibroblasts. In patients with nephronophthisis, the synthesis of EPO is decreased.

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Causes

All of the disease variants of the nephronophthisis–medullary cystic kidney disease complex are caused by defects in different genes at distinct chromosomal loci.

Table. Molecular Genetic Features of the Nephronophthisis–Medullary Cystic Kidney Disease Complex (Open Table in a new window)

Disease

Inheritance

 

Chromosome

Gene, Protein

Genetic Defect

NPH1

Autosomal recessive

 

2q13

NPHP1, nephrocystin-1

Homozygous deletion, heterozygous deletion

NPH2

Autosomal recessive

 

9q31

NPHP2/INV, inversin

Recessive mutations

NPH3

Autosomal recessive

 

3q22

NPHP3, nephrocystin-3

Recessive mutations

NPH4

Autosomal recessive

 

1p36

NPHP4, nephroretinin

Point mutations

NPH5

Autosomal recessive

 

3q21

NPHP5, nephrocystin-5

Truncations

NPH6

Autosomal recessive

 

12q21

NPHP6, nephrocystin-6

Truncations

NPH7

Autosomal recessive

 

16p

NPHP7, nephrocystin-7

Unknown

NPH8

Autosomal recessive

 

16p

NPHP8, nephrocystin-8

Truncations, missense

NPH9

Autosomal recessive

 

17q11

NPHP9, nephrocystin-9

Missense

NPH11

Autosomal recessive

 

8q22.1

NPHP11, nephrocystin-11

Missense

NPH1L

Autosomal recessive

 

22q13

Nephrocystin-1L

Deletion

MCKD1

Autosomal dominant

 

1q21

MUC1,

mucin1

Missense

MCKD2

Autosomal dominant

 

16p12*

UMOD, Uromodulin

Missense

*Co-localizes with familial juvenile hyperuricemic nephropathy

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