Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

[Prophylactic parathyroidectomy for familial parathyroid carcinoma]. / Das familiäre Nebenschilddrüsenkarzinom Indikation zur prophylaktischen Parathyreoidektomie?

In contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10-15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.

[Endocrinological findings in endocrine orbitopathy]. / Endokrinologische Befunde bei der endokrinen Orbitopathie.

Carl-Adolph von Basedow described the typical clinical features of immune-mediated hyperthyroidism (tachycardia, proptosis, goiter) in 1840 and termed it the "Merseburg trias". Graves' disease is an autoimmune disease with thyroidal and extra-thyroidal manifestations such as endocrine orbitopathy, which is caused by a dense lymphocytic infiltrate. A genetic predisposition combined with so far unidentified environmental factors and a complex immunological process seem to be important for its pathophysiology. The pathognomonic histopathophysiological picture is characterised by the typical lymphocytic infiltration of the ocular muscles and retrobulbar connective and adipose tissues leading to the classical exophthalmus. No specific therapy is available. The goal of therapy is therefore the correction of the hyperthyroidism and inhibition of the immune-mediated orbital inflammation which can be achieved by early interdisciplinary team work of endocrinologists, ophthalmologists and radiation therapy.

Delay of growth and development in children with bronchial asthma, atopic dermatitis and allergic rhinitis.

The elevated incidence of short stature (body height < (-)x - 2s), skeletal retardation and delayed puberty in children with bronchial asthma or atopic dermatitis is generally attributed to the severity of the disorder. However, a series of findings indicate a causal influence of the atopy and the existence of atopic skeletal retardation per se.The observation that children with atopic disorders, whether bronchial asthma, atopic dermatitis or allergic rhinitis, exhibit a rate of short stature that is twice to five times higher than normal indicates atopic and thus genetically determined influences. The elevated prevalence of short stature associated with allergic rhinitis is especially significant, as this disorder cannot be included among the severe chronic disorders. The fact that skeletal retardation is more prevalent in boys than in girls by a ratio of about 2:1 and that a significantly more marked retardation of bone maturation is found in atopic in comparisons with non-atopic asthmatics also lend support to this postulation. The clinical relevance of atopic growth retardation is also supported by the close interaction of pathophysiological basal mechanisms of bone metabolism and the atopy status. Thus the local growth factor prostaglandin E(2) (PGE(2)), which is important for bone metabolism, is also a messenger substance for the immediate and late allergic reaction. The platelet-activating factor (PAF), as one of the strongest mediators in the pathogenesis of allergic disorders, influences the PGE(2) synthesis in the osteoblasts. These relationships show that atopy-dependent imbalances in the complex system of local and systemic growth factors can certainly lead to disturbance of skeletal maturation which may delay growth and development in atopic children. In order to verify these assumptions it is necessary to research the interaction of local growth factors (particularly the roles of PGE(2), PAF and IGF I) in the skeletons of children of short stature suffering from atopic disorders. This should also include the possible effects on the overall hormonal factors influencing bone maturation. Atopy should be included in the differential diagnosis programme to clarify growth and development disturbances.

[Investigation of growth prognosis in asthmatic children]. / Untersuchungen zur Wachstumsprognose asthmakranker Kinder.

The objective of the present study was the ascertainment of correct data related to growth prognosis in asthmatic children. For this purpose, 210 young asthmatics including 153 males and 57 females ranging in age from 1.7 to 18.9 years were evaluated. Data were specified for the parameters: chronological age (CA); bone age (KA); height age (LA); height (KH); severity of illness; target adult height (GZG) and predicted adult height (PEG). Among this group, 5.9 % of the boys and 3.5 % of the girls, were found to be of small stature (KH < - 2 s). This corresponds to about 2.5 and 1.5 times the average in a normal distribution. Children with the highest severity of illness showed the strongest negative deviation for the KH-SDS values (boys - 0.59 plus minus 1.1, girls - 0.97 plus minus 0.8). This proved to be statistically significant for females. Development of CA, KA and LA continued unremarkably until the age of 4 years. From age 5, partially a significant growth retardation of KA and LA could be observed in both sexes. To age 16, KA values and, after that LA values, were more strongly affected. Comparison of the GZG and PEG average values within the degree of severity groups made it clear that the PEG values for both sexes, independent of the severity of illness, were without exception, smaller than the GZG. The differences of both parameters proved to be statistically significant for the group with the most severe symptoms of the boys (180.8 plus minus 6.5 cm to 175.8 plus minus 6.2 cm, p < 0.01) and for the entire groups of both sexes (boys 180.2 plus minus 5.3 cm to 178.6 plus minus 7.3 cm, p < 0.05, girls 167.7 plus minus 4.4 cm to 165.8 plus minus 6.8 cm, p < 0.05). However, a separate comparison of GZG and PEG average values, respectively, among the severity groups showed no significant differences. The results argue for a growth-inhibiting influence from bronchial asthma. The cause has to be severity of illness but direct effects of the atopy on skeletal development is also taken in consideration. Confirmation of these findings requires investigation of a larger group of asthmatics and clarification of the pathophysiological processes in the growing skeletons of atopic children.

["Physiological" and "neoplastic" C-cell hyperplasia of the thyroid. Morphologically and biologically distinct entities?]. / "Physiologische" und "neoplastische" C-Zell-Hyperplasien der Schilddrüse. Morphologisch und biologisch distinkte Entitäten?

C-cell hyperplasia (CCH) occurs regularly in the setting of type 2 multiple endocrine neoplasia (MEN2), either separately or in association with medullary thyroid carcinoma (MTC). It can also accompany sporadic MTC and appear without any tumour association. To test the practicability of the terms "physiologic" and "neoplastic", 18 cases with incidental sporadic, non-MTC associated CCH were investigated and the morphological patterns were described. We found CCH of various degrees, including so-called neoplastic CCH. In 16 of the 18 cases, a MEN2 setting could be ruled out by mutation analysis of the RET proto-oncogene. Morphologically, one can not distinguish with certainty between sporadic and hereditary or reactive and tumour-associated CCH. While MEN2-associated CCH can be regarded as true preneoplasia, sporadic CCH possesses variable biologic potential. The preneoplastic potential of sporadic CCH is still obscure. A pure morphological distinction between "physiologic" and "neoplastic" CCH regardless of the RET status should not be used.

Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant?

OBJECTIVE: Familial isolated primary hyperparathyroidism (FIHP) is defined as hereditary primary hyperparathyroidism without the association of other diseases or tumors. Linkage analyses suggest that different genotypes can lead to the same phenotype of primary hyperparathyroidism. Hereditary syndromes associated with primary hyperparathyroidism are multiple endocrine neoplasia type 1 and type 2 (MEN 1 and MEN 2). In MEN 1, multiple parathyroid adenomas occur in more than 90% of the patients. Therefore, it has been suggested that FIHP could represent a variant or partial expression of MEN 1. DESIGN: We report on a large FIHP kindred with a MEN1 gene mutation. Nineteen family members (aged 10 to 87 years) were screened. Furthermore, statistical comparison by Fisher's exact tests of FIHP families with MEN1 gene mutations and MEN 1 families with two or more endocrinopathies was carried out to investigate genotype-phenotype correlations. METHODS: Mutational analysis of leucocyte DNA was carried out by direct sequencing of the complete coding region of the MEN1 gene. Screening of MEN 1 manifestations was carried out by determination of serum calcium, phosphate, parathyroid hormone, prolactin, ACTH, cortisol, IGF-I, gastrin, glucose, insulin, glucagon, serum potassium, aldosterone, plasma renin and urinary hydroxyindoleacetic acid. RESULTS: We detected an in-frame deletion mutation in exon 8 of the MEN1 gene resulting in the deletion of one glutamine acid residue at position 363. It was found in eight individuals. Two of these family members (aged 42 and 60 years) were operated for primary hyperparathyroidism, and three (aged 13 to 40 years) showed mild hypercalcemia and parathyroid hormone levels within the upper normal range or slightly elevated, without any clinical symptoms. Two individuals (aged 12 and 19 years) were normocalcemic. One could not be tested. None of them had clinical evidence of other MEN 1 manifestations. Statistical comparison of the mutation types in families with FIHP and families with two or more MEN 1-associated endocrinopathies reported in other studies reveals a significant difference. In families with FIHP, missense/in-frame mutations have been found in 87.5% of cases whereas in families with tumors in various endocrine glands these mutation types occur much less frequently (21-34%, P<0.05). CONCLUSIONS: These studies indicate that FIHP can represent a partial MEN 1 variant and is often caused by missense/in-frame mutations.

Differential diagnosis of calcitonin-secreting neuroendocrine carcinoma of the foregut by pentagastrin stimulation.

BACKGROUND AND AIMS: This study assessed the suitability of pentagastrin stimulation in hypercalcitoninaemia for differential diagnosis of neuroendocrine carcinoma of the foregut. PATIENTS: A prospective institutional study (March 1997-September 1999) was conducted involving all patients admitted to the pneumological and general surgical wards for small cell lung cancer (SCLC) or primary medullary thyroid carcinoma (MTC). Basal and stimulated serum calcitonin levels were measured using an improved immunoradiometrical assay for the monomeric form of calcitonin. RESULTS: Increased basal calcitonin levels were noted in six non-MTC patients (one mediastinal and one laryngeal neuroendocrine carcinoma, and four SCLCs). Because of chronic renal failure, one SCLC patient had to be excluded. The remaining five non-MTC patients with normal renal function were compared to eight primary MTC patients. In terms of pentagastrin stimulation, an increase in serum calcitonin levels of less than twofold the baseline significantly correlated with both non-MTC (r=0.85; P=0.005) and SCLC (r=0.81; P=0.024). Immunostaining of tissue specimens for calcitonin was positive in the patients with mediastinal and laryngeal neuroendocrine carcinoma and in all eight patients with primary MTC, but was negative in the two SCLC patients with adequate tissue samples. CONCLUSIONS: Irrespective of the pathophysiological background, pentagastrin stimulation affords a differential diagnosis in neuroendocrine carcinoma of the foregut when chronic renal failure is excluded.

Hypercalcitoninemia in a sporadic asymptomatic neuroendocrine tumor of the pancreatic tail.

BACKGROUND/AIM: Asymptomatic neuroendocrine tumors of the gastroenteropancreatic tract represent a significant challenge in terms of postoperative monitoring. METHODS: A case report of a calcitonin-secreting asymptomatic neuroendocrine tumor of the pancreatic tail is presented. RESULTS: Hypercalcitoninemia was noted in the 76-year-old Caucasian man who had a recurrent neuroendocrine tumor of the pancreatic tail. Upon pentagastrin stimulation, basal calcitonin increased only moderately from 82.3 (<10) to 100.9 and 125 pg/ml after 2 and 5 min, respectively. Surgical removal of the neuroendocrine tumor resulted in postoperative normalization of both basal and stimulated serum calcitonin levels. On immunohistochemistry, the neuroendocrine tumor was positive for calcitonin. CONCLUSION: Routine measurements of serum calcitonin might be a highly sensitive adjunct capable of identifying a subset of neuroendocrine tumors in which calcitonin monitoring may aid in the early detection of postoperative recurrence.

Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis.

BACKGROUND: The aim of this study was to identify better prognostic parameters for normalization of serum calcitonin in medullary thyroid carcinoma (MTC) patients. METHODS: In 73 patients who had undergone systematic lymph node dissection for MTC between September 1995 and November 1998, preoperative (n = 29) and postoperative (n = 65) basal and stimulated serum calcitonin were correlated with the pTNM classification and the number of positive regional lymph nodes and compartments. RESULTS: In contrast to pT and M, there was a significant correlation between postoperative calcitonin and the pN category. With rising numbers of positive lymph nodes (0, 1-9, 10-19, and > or = 20), postoperative basal and stimulated calcitonin increased exponentially, and gross distant metastases (M1) occurred more frequently (0%, 4%, 13%, and 50%; P = 0.013). Conversely, serum calcitonin was less often normalized (65%, 31%, 0%, and 0%; P = 0. 003). There was a close correlation between the number of positive lymph nodes and the number of affected compartments (P < 0.001; r = 0.93). Irrespective of location, involvement of 10 or more lymph nodes and more than 2 compartments precluded normalization of serum calcitonin. CONCLUSIONS: Quantitative lymph node analysis of MTC improves prediction of calcitonin normalization. When more than two compartments are involved, normalization of serum calcitonin cannot be attained. Surgery should then be less extensive and more directed at preventing local complications.

HCG induced hyperthyreosis in germ cell cancer.

Human germ cell tumors have the unique capacity for totipotential differentiation. AFP (the product of normal yolk sac) and HCG (produced by trophoblastic tissues) are frequently produced by germ cell tumors. The a-subunit of the glycoprotein HCG is identical to that of several pituitary glycoprotein hormones (e.g. TSH, LH, FSH), whereas the b-subunit of HCG, TSH, LH and FSH is homologous but distinct in the terminal amino acid sequence suggesting that HCG is part of a superfamily of gestational hormones. However, the role of TSH within this hormone superfamily is still not yet established. A 24-year old patient was admitted to our clinic because of a widespread recurrence of a germ cell tumor (stage IIIC, Lugano classification). The routine hematologic and blood chemical tests were normal, yet, an elevated HCG was found. In addition, increased levels of the thyroid hormones FT3 and FT4 were seen, although, this was not associated with clinical symptoms of a hyperthyreosis. There was no history of hyperthyreosis and thyroidal autoantibody screening revealed normal titers. An ultrasound examination of the thyroid gland showed no abnormalities and no iodine exposure had occurred during the last months. To mobilize peripheral stem cells (PBSC) he was initially treated with paclitaxel (175 mg/m2) and ifosfamide (8.000 mg/m2)) followed by apheresis of PBSC. The patient was then entered in our phase-II-study for relapsing germ cell carcinomas using a high-dose chemotherapy regime (paclitaxel 175 mg/m2, ifosfamide 9.000 mg/m2, carboplatin 900 mg/m2, etoposide 900 mg/m2) with subsequent retransfusion of collected stem cells. Due to cranial metastases an cranial irradiation was also performed. After three courses of this protocol an excellent partial remission of the tumor lesions was achieved and the HCG value dramatically decreased. Due to elevated thyroidal hormones, the patient was initially treated with thiamazole (20 mg) resulting in decrease of the thyroidal hormones. Thus, the thiamazole dose was reduced to 5 mg and then omitted. The decrease of the thyroidal hormones FT3 and FT4 strongly correlated with the reduction of HCG values (r2 0.91 and 0.77, p < 0.0008). To date there is only slight evidence that enhanced HCG levels may cause, at least in part, a hyperthyreosis (e.g. gestational hyperthyreosis), however, the underlying biochemical mechanism still remains unclear. In this case report we have demonstrated a clear positive correlation between HCG levels and thyroidal hormones in a patient with germ cell tumor suggesting a direct stimulation of hormone producing thyroidal cells by HCG, however, this was not associated with clinical symptoms of hyperthyreosis. Currently, several in vitro studies are underway in our laboratory to further elucidate the biochemical mechanisms of HCG induced hyperthyreosis.

[Effect of the beta-2 mimetic drug terbutaline of growth hormone secretion in prepubertal asthmatic children]. / Zum Einfluss des Beta-2-Mimetikums Terbutalin auf die Wachstumshormonsekretion präpubertärer asthmakranker Kinder.

Asthmatics display a tendency to retarded growth and hyposomia in childhood. The reasons for this are not yet clear, although the atopic disposition seems to occupy a key role. It is a known fact that stimulation of the beta-2 receptors results in inhibiting growth hormone secretion. The purpose of our study was to find out whether the beta-2 mimetic terbutalin, often used in asthma therapy, exercises a negative influence on the spontaneous release of growth hormone in children suffering from asthma. The growth hormone release was studied in 10 prepuberal children suffering from atopic asthma who received intravenous therapeutic doses of terbutalin: testing was done for a total period of 24 hours before and during administration. Terbutalin effected significant inhibition of growth hormone secretion merely during the waking phase (6.2 +/- 1.0 to 3.7 +/- 0.7 ng/ml), but not during the sleep phase (13.1 +/- 1.8 to 12.5 +/- 2.0 ng/ml) and the 24-hour period (11.0 +/- 1.0 to 9.8 +/- 1.5 ng/ml). There was also no significant influence on the average group value for the maximum growth hormone peak (40.8 +/- 9.5 to 42.7 +/- 11.0 ng/ml). These results point to a short-term inhibition of growth hormone secretion, exercised by intravenously administered terbutalin. Terbutalin does not seem to be responsible for any clinically relevant inhibition of growth and development.

Multiple intracranial lipoma: a case report.

We report on a male epileptic patient, presently 27 years old, who has suffered complex-partial attacks for 19 years. Under treatment with carbamazepine the seizures were completely controlled. In addition, the patient exhibited partial hypopituitarism. CT and MRI revealed the presence of 2 lipomas, one located within the optico-chiasmatic cistern and the other one in the medial temporal lobe. To our knowledge, this combination of the generally rare lesions has not been described yet.

[Inhibition of growth hormone secretion by theophylline in asthmatic children]. / Hemmung der Wachstumshormonsekretion durch Theophyllin bei asthmakranken Kindern.

Children suffering from asthma display a tendency to retarded growth and development, which also includes bone structure. The reason for this phenomenon has not been clarified. There seems to be an adaptative regulatory hypersomatotropism which can be regarded as a disturbance of peripheral growth hormone activity. We studied the question whether this is influenced by theophylline, a preparation often used in the treatment of asthma, since theophylline has been accused of growth hormone inhibition as a result of in vivo studies in adults. In 9 prepubertal boys suffering from atopic asthma we determined the growth hormone concentrations during 24 hours each before and during intravenous administration of theophylline. With this dosage the median values of the 24-hour profile (10.3 +/- 1.5 to 5.2 +/- 0.9 ng/ml), the 8-hour sleep phase (12.7 +/- 1.9 to 5.7 +/- 1.0 ng/ml) and of the maximal growth hormone peak (38.9 +/- 7.0 to 17.6 +/- 2.8 ng/ml) were significantly lower than on the first day on which theophylline was not administered. The multiple possibilities by which theophylline may be exercising this effect, are discussed. Prospective long-term clinical studies will have to clarify whether the effect is clinically significant.

Resynchronization of the circadian corticosterone rhythm after a light/dark shift in juvenile and adult mice.

Most of the extensive literature concerning the resynchronization of circadian rhythms after a Zeitgeber shift is devoted to the dependence of resynchronization on the mode of the shift and the strength of the Zeitgeber, as well as on the circadian function investigated. Ontogenetic influences have rarely been investigated. Therefore, we studied the resynchronization of several circadian rhythms in juvenile and adult female laboratory mice. We present here the results concerning the corticosterone rhythm. The daily rhythms were determined as transverse profiles (2-h intervals) before as well as 3, 7, and 14 days after an 8-h phase delay of the light/dark cycle produced by a single prolongation of dark time. The corticosterone concentration in serum was determined radioimmunologically. In the control animals the daily patterns were bimodal, with main maxima at the end of the light time and secondary ones just after lights on. Ontogenetic differences were small. In adult mice the amplitude was slightly increased due to an increase in the maximum values, and the time of highest hormone concentrations was slightly phase advanced. In juvenile mice, a distinct daily pattern with a phase position in relation to the light/dark cycle corresponding to that of control animals was present on the 3rd day after the Zeitgeber shift. The daily mean as well as the minimum and maximum values increased initially and reached the values of control animals during the second week. In adult animals, a pronounced daily rhythm with the normal phase position was present only at the 7th postshift day. The amplitude, daily mean, and maximum values were decreased, and the minimum values were increased. The initial values were not reached even after 2 weeks. The results show that resynchronization was faster in juvenile mice compared with adult mice. As a possible cause for the observed age-related differences, a not yet stabilized phase-coupling between various circadian rhythms is supposed.

[Increase in spontaneous growth hormone secretion in asthmatic children--a symptom of atopic disposition?]. / Steigerung der spontanen Wachstumshormon-Sekretion bei asthmakranken Kindern--Ein Symptom der atopischen Disposition?

BACKGROUND: Asthmatic children tend towards hyposomia. Although quite a number of suggestions have been made, the real cause of this phenomenon has not yet been revealed. Investigation of the growth hormone secretion and the IGF-I serum levels aims at clarifying whether an atopy-caused disturbance in the interaction between both the hormones is responsible for retardations in the growth and development of asthmatic children. METHODS: In 19 prepubertal extrinsic asthmatics the spontaneous growth hormone secretion was reviewed in form of a 24 h-profile. In addition, the IGF-I serum levels were measured. RESULTS: With a mean 24 h-secretion of 10.7 +/- 1.0 ng/ml and a maximum growth hormone peak of 39.5 +/- 5.8 ng/ml prepubertal extrinsic asthmatics showed an increased hormone secretion which, however, could not be observed with all the children. The IGF-I mean values were in 11 asthmatics within the normal range, decreased in 5 cases and increased in only 3 children.

[Organic hyperinsulinism. Clinical aspects--diagnosis--therapy]. / Organischer Hyperinsulinismus. Klinik--Diagnostik--Therapie.

It is reported on the clinical experiences in the care of 19 patients with insulinoma. The relatively simple proof of the existence of an insulinoma which is possible by the determination of insulin is performed by the recognition of a pathognomonic insulin--blood glucose--quotient in fasting state and in the fasting test, respectively. Stimulation tests are less evident and do not lead to any further clinically relevant information. The difficulty of the diagnosis consists in the localisation of the tumour. Without clinically urgent necessity an operation without localisation of the tumour should not be performed.

[Hiob syndrome. A case report of multiple endocrine neoplasia]. / Das Hiob-Syndrom. Ein kasuistischer Beitrag zur multiplen endokrinen Neoplasie.

It is reported on a now 48-year-old male with a multiple endocrine neoplasia (MEN I). The most impressive symptomatology issued from a relapsing organic hyperinsulinism the cause of which were multiple islet cell tumours. Up to now the hyperparathyroidism was not mastered by the removal of two adenomas of the parathyroid gland. As third fact in this clinical picture, called also Hiob syndrome, the hypophyseal manifestation developed in form of a space occupation with a hypersomatotropism, the course and final clarification of which are still open.

[Homocystinuria]. / Homozystinurie.

It is reported on a female patient with a classical homocystinuria who showed all typical symptoms of the cystathionine-synthesis-insufficiency, such as tall stature, phacetomy, arachnodactyly, kyphoscoliosis, generalized osteoporosis and thromboembolisms. While homocystin in the blood plasma and the urine could be proved only in the patient, the concentration of plasma methionine was much increased also in the clinically completely inconspicuous sister.