C-Type Natriuretic Peptide and Achondroplasia
C-Type Natriuretic Peptide and Achondroplasia
Achondroplasia and hypochondroplasia are the most common forms of dwarfism. Recent studies
 have shown that a small hormone called C-type natriuretic peptide (CNP) is an important
 regulator of linear growth. The investigators believe that genetic abnormality that causes
 achondroplasia and hypochondroplasia also disrupts CNP signaling, which may contribute to the
 growth problem. The investigators propose to look at levels of this and other closely related
 hormones in children and adults with achondroplasia or hypochondroplasia to see if they are
 different from levels in healthy people. The investigators hypothesis is that CNP levels are
 elevated in children with achondroplasia or hypochondroplasia, compared the healthy
 population. Another hypothesis is that CNP levels are not elevated in adults with
 achondroplasia or hypochondroplasia, since adults have no growth-plate cartilage. By studying
 the potential role of the CNP system in achondroplasia and hypochondroplasia, not only will
 the investigators provide further insight into the pathophysiology of these common syndromes,
 the investigators will also provide greater insight into the regulation of normal linear
 growth.
Achondroplasia is the most common form of dwarfism and is characterized by short limbs with
 the thighs and upper arms being the most affected. Achondroplasia is also associated with a
 narrowing of the foramen magnum and spinal stenosis. Hypochondroplasia is a related, but less
 severe form of dwarfism that does not have the neurologic problems. Achondroplasia and
 hypochondroplasia are caused by mutations in the fibroblast growth factor receptor-3 (FGFR-3)
 gene that causes constitutive activation of the receptor. FGFR-3 signals primarily through
 the MAP kinase pathway, which is overactivated in growth plate chondrocytes in
 achondroplasia. C-type natriuretic peptide (CNP) is a hormone that is produced and acts in
 the growth plate as a potent positive regulator of linear growth. CNP signals through
 natriuretic peptide receptor-B (NPR-B), generating cGMP. Studies in mice show that activation
 of the MAP kinase pathway inhibits signaling through NPR-B. Hence the achondroplasia
 phenotype may be due in part to inhibition of CNP signaling. Conversely, CNP intracellular
 signaling inhibits the MAP kinase pathway and CNP analogs are being studied as a potential
 specific therapy for achondroplasia. The objective of this project is to define the state of
 the CNP system in children and adults with achondroplasia or hypochondroplasia. Our
 hypotheses are 1) blood levels of CNP and its aminoterminal propeptide (NTproCNP) are
 elevated and blood levels of cGMP are reduced in children with achondroplasia or
 hypochondroplasia, due to inhibition of NPR-B; 2) CNP and NTproCNP levels are normal in
 adults with achondroplasia and hypochondroplasia, due to their lack of growth plate
 cartilage; and 3) as in healthy children, NTproCNP levels predict height velocity in children
 with achondroplasia or hypochondroplasia. These hypotheses will be addressed with two
 specific aims. Specific aim 1 is to determine plasma levels of CNP, NTproCNP, and cGMP in
 children and adults with achondroplasia or hypochondroplasia. Specific aim 2 is to determine
 if NTproCNP levels correlate with height velocity in children with achondroplasia or
 hypochondroplasia.

 The study is an observational, cross-sectional/partially longitudinal study of children and
 adults with achondroplasia or hypochondroplasia. Children will be seen as part of routine
 clinic visits. Children seen more than once during the study period will provide longitudinal
 data. Adult subjects with achondroplasia or hypochondroplasia will be studied a single time.
 Data collected will include anthropometrics, information on neurologic complications of
 achondroplasia, and blood levels of CNP, NTproCNP, and cGMP. We anticipate 100 subjects will
 be recruited, with about 20 being studied as many as three times during the course of the
 study.

 By studying the potential role of the CNP system in achondroplasia and hypochondroplasia, not
 only will we provide further insight into the pathophysiology of these common syndromes, we
 will also provide greater insight into the regulation of normal linear growth.
Inclusion Criteria:

 -  a diagnosis of achondroplasia or hypochondroplasia