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There is no single unifying trait for these disorders.   Some have their genetic defect well characterized.  Others are still waiting for the discovery of the gene or genes which are damaged.  The diagnosis requires careful clinical laboratory evaluation and may require testing for enzymes that are only available in research laboratories.  Biopsy diagnosis may play an important role, not only in establishing the diagnosis, but providing fresh tissue for molecular and enzyme studies.

Acrodermatitis Enteropathica
Alagille Syndrome
Alkaptonuria (Ochronosis)
Alpha-1-Antitrypsin Deficiency
Alport Syndrome
Bannayan-Zonana Syndrome
Canavan Disease
Common Variable Immunodeficiency
Cowden Syndrome
Cystic Fibrosis
Diabetes Insipidus
Down Syndrome (Trisomy 21)
Ectodermal Dysplasia
Ehlers-Danlos Disease
Fabry Disease
Gaucher Disease
Juvenile Hyaline Fibromatosis (Murray-Puretic Syndrome)
Necrolytic Migratory Erythema
Ochronosis (Alkaptonuria)
Osteogenesis Imperfecta
Proteus Syndrome
Refsum's Disease
Restrictive Dermopathy
Retinitis Pigmentosa
Rubinstein-Taybi Syndrome
Scurvy (Vitamin C Deficiency)
Shwachman-Diamond Syndrome
Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH)
Tuberous Sclerosis
von Hippel-Lindau Disease
Williams Syndrome

The Human Genome Project will soon have the complete genetic sequence of 3 billion base pairs of DNA encoding for about 100,000 genes. Already, many genes for diseases have been uncovered. As of this writing, it is estimated that 1% of all newborn infants harbor some chromosomal abnormality and 5% of individuals below the age of 25 yrs may develop a serious disease with a significant genetic component.

Genetic disorders are frequently the result of an abnormal gene leading to an enzyme or protein defect. There are also disorders which are termed multifactorial inheritance, resulting from the combined actions of both the environment and genetic component. Criteria for this class of disorders are presented in the following table.

Criteria Description
Risk of expression Conditioned by number of mutant genes inherited
Risk is greater in siblings of patients having severe expressions of the disease
Rate of recurrence Same for all first degree relatives of the affected individual
Ranges from 2-7%
Likelihood of identical twins affected Significantly <100% but greater than the chance that both non-identical twins will be affected
Risk of recurrence in subsequent pregnancies Depends upon the outcome in previous pregnancies
If one child is affected, there is up to a 7% chance that the next child will be affected
After two siblings affected, the risk rises to 9%
Expression of a trait May be continuous (lacking a distinct phenotype) or discontinuous (with a distinct phenotype)
Diabetes is discontinuous, the disease is expressed only when the combined influences of genes and environment cross a threshold, as when the glucose levels increase

Some multifactorial disorders are listed below.

Cleft lip or cleft palate
Congenital heart disease
Coronary heart disease
Diabetes mellitus
Pyloric stenosis


Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
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Telomere length, telomerase activity, and expression of human telomerase reverse transcriptase mRNA in growth plate of epiphyseal articular cartilage in femoral head during normal human development and in thanatophoric dysplasia.

Morita M, Nakanishi K, Kawai T, Fujikawa K.

Department of Orthopaedic Surgery, National Defense Medical College, Tokorozawa, Japan.
Hum Pathol. 2004 Apr;35(4):403-11. Abstract quote  

Telomeres are important in chromosome structure and function, protecting against their degradation. However, few studies have examined telomeres in growth plates within articular cartilage during normal development. We investigated frozen sections that were obtained from 57 reference autopsy cases (aged from 16 weeks of gestation to 91 years) and from 2 patients with thanatophoric dysplasia.

In the reference cases, telomere length was significantly longer in growth plates obtained from the 10 cases that were aged from 16 weeks of gestation to 10 years than in those from 47 of the adult cases (aged 20 to 91 years). In fetal, neonatal, and child cases, telomerase activity was significantly higher in the hypertrophied zone (HZ) in growth plates than in the other 3 zones. The hTERT mRNA staining intensity (staining area) was stronger (larger) in HZ and the proliferating zone than in the calcified zone and resting zone.

In thanatophoric dysplasia, telomere length and telomerase activity were short and low, respectively, compared with those of normal growth plates at an equivalent age, and expression of hTERT mRNA was negative or weakly positive in all 4 zones within growth plates. These results suggest that telomere length and telomerase activity have significant effects in the growth plates of articular cartilage, particularly at developmental ages from fetus to child.

We speculate that short telomere length and low telomerase activity may be important for chondrocyte differentiation in rhizomeric shortening of the limbs in thanatophoric dysplasia.




Ichthyosis and keratotic follicular plugs containing dystrophic calcification in newborns: distinctive histopathologic features of x-linked dominant chondrodysplasia punctata (Conradi-Hunermann-Happle syndrome).

Hoang MP, Carder KR, Pandya AG, Bennett MJ.

Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9073, USA.
Am J Dermatopathol. 2004 Feb;26(1):53-8. Abstract quote  

Prior to the recent characterization of the enzymatic defect and identification of the involved gene, the histopathology of X-linked dominant chondrodysplasia punctata (Conradi-Hunermann-Happle syndrome or CDPX2) has been described under various names including calcinosis universalis, chondrodystrophia calcificans congenita, Conradi disease, and Conradi-Hunermann syndrome.

We present two newborns with characteristic ichthyosiform erythroderma noted at birth. Radiographs demonstrated chondrodysplasia punctata in one patient. Although the x-ray performed at birth was negative in the other patient, sterol analyses of the keratotic scales were diagnostic for CDPX2. Skin biopsies from both patients showed thick laminated orthokeratosis and prominent keratotic follicular plugs containing dystrophic calcification. We also retrospectively examined 20 cases of various types of ichthyosis seen over a 23-year period at our institution. Intracorneal calcium deposition was not seen in any of these cases.

As demonstrated by our cases and review of the literature, dystrophic calcification in the keratotic plug is a distinctive histopathologic feature of Conradi-Hunermann-Happle syndrome in newborns and is not seen in other known forms of ichthyoses.

Trichorhinophalangeal Syndrome Type I Clinical and Molecular Characterization of 3 Members of a Family and 1 Sporadic Case

Cornelia Sabine Seitz, MD; Hermann-Josef Lüdecke, PhD; Nicola Wagner, MD; Eva-Bettina Bröcker, MD; Henning Hamm, MD

Arch Dermatol. 2001;137:1437-1442 Abstract quote

Trichorhinophalangeal syndrome type I (TRPS I) is a rare autosomal dominant disorder clinically characterized by sparse and slow-growing hair, pear-shaped nose, elongated philtrum, thin upper lip, and bone deformities, in particular, cone-shaped epiphyses of the phalanges. Very recently, the responsible gene TRPS1 has been cloned on human chromosome 8q24.

We describe a mother and her 2 daughters and a female patient with a sporadic case of TRPS I. In the familial case, mutation analysis showed an insertional mutation at position 2480 of the TRPS1 gene leading to a premature translational stop. Careful clinical examination showed craniofacial and radiologic features typical of TRPS I, including short stature, in all 3 affected individuals. Additionally, they presented with a receded triangular medio-occipital hairline, which has not been described in TRPS I so far. In the sporadic case, we identified a single base deletion at position 2110 of the TRPS1 gene leading to frameshift and premature translational stop at codon 766. The patient presented with the typical TRPS I phenotype but was of normal stature.

The TRPS I is characterized by variable clinical expression of the triad of hair, craniofacial, and skeletal abnormalities. New genetic approaches, including mutation analysis, now allow identification of carriers of the TRPS1 gene mutations.



Ultrastructural examination of the axillary skin biopsy in the diagnosis of metabolic diseases

Caroline M. Abramovich, MD, Richard A. Prayson, MD, James T. McMahon, PhD, and Bruce H. Cohen, MD

Hum Pathol 2001;32:649-655 Abstract quote

There is little information in the literature regarding the usefulness of ultrastructural examination of axillary skin biopsies in the evaluation of metabolic diseases.

This is a retrospective clinicopathologic review of 143 patients who underwent axillary skin biopsies as part of evaluations for metabolic disease. Twenty-three (16%) had abnormalities, classified as follows: mitochondrial (n = 12), lysosomal (n = 6), increased glycogen (n = 3), nonspecific cytoplasmic inclusions (n = 2), ceroid lipofuscinosis (n = 1), and intradermal giant cells containing vacuoles and tubular inclusions (n = 1). Muscle biopsies were performed in 13 of the 23 patients; 11 showed abnormalities, including those related to mitochondria (n = 4) and other nonspecific changes (n = 7). Two patients underwent postmortem examination. Follow-up was available in 21 patients. A clinical or biochemical diagnosis was reached in 11 patients: metachromatic leukodystrophy (n = 2), electron transport chain abnormalities (n = 2), glutaric aciduria type II (n = 1), Unverricht disease (n = 1), Lennox-Gastaut syndrome (n = 1), ketotic hypoglycemia of childhood (n = 1), probable Leigh disease (n = 1), 5-methyl tetrahydrofolate homocystine methyltransferase deficiency (n = 1), and pyruvate dehydrogenase deficiency (n = 1). Of the 120 patients with negative skin biopsy results, 29 had abnormal findings on muscle (n = 27), nerve (n = 7), or brain (n = 3) biopsies. One patient had an abnormal heart biopsy result, and 3 patients underwent postmortem examinations. Follow-up was obtained in 27 of 29 patients. Diagnoses were achieved in 15 patients: electron transport chain abnormalities (n = 5), cortical dysplasia (n = 3), myoclonic epilepsy (n = 1), leukodystrophy (n = 2), Pallister-Killian mosaic syndrome (n = 1), Rett syndrome (n = 1), Landau-Kleffner syndrome (n = 1), and mitochondrial cardiomyopathy (n = 1).

In conclusion, axillary skin biopsy is helpful in the evaluation of some causes of metabolic disease, but often the findings are nonspecific. A negative biopsy result does not rule out the possibility of metabolic disease, but a positive result may provide direction for further evaluation.

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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Inborn Errors of Metabolism-General term sometimes used to refer to this group of disorders.

Newborn Screening

Pregnancy Laboratory Testing

Basic Principles of Disease
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Commonly Used Terms
This is a glossary of terms often found in a pathology report.

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Last Updated February 14, 2006

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